Furans, benzofurans, and thiophenes useful in the treatment of insulin resistance and hyperglycemia

ABSTRACT

This invention provides compounds of Formula I having the structure                    
     wherein 
     R 1  and R 2  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, halogen, perfluoroalkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, thienyl, furyl, phenyl or phenyl substituted with trifluoromethyl, chloro, methoxy, or trifluoromethoxy; 
     R 3  and R 4  are each, independently, hydrogen, carboxyl, hydroxyl, hydoxyalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, alkanoyloxy of 2-7 carbon atoms, perfluoroalkanoyloxy of 2-7 carbon atoms, arylalkoxy of 7-15 carbon atoms, aryloxy of 6-12 carbon atoms, aroyloxy of 6-12 carbon atoms, aryloxycarbonyl of 7-13 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, perfluoroalkoxycarbonyl of 2-7 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, tetrazolyl, mercapto, nitrile, nitro, amino, —NHSO 2 CF 3 , carbamoyl, carboxyaldehyde, halogen, acylamino, 3-hydroxy-cyclobut-3-ene-4-yl-1,2-dione, pyridyl, isoxazolyl, pyrimidyl or pyrimidyl substituted with mercapto, or tetronic acid; 
     R 5  is hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, naphthalenylmethyl, benzyl or benzyl substituted with halogen, 
     R 6  and R 7  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or perfluoroalkyl of 1-6 carbon atoms, or R 6  and R 7  may be taken together as a diene unit having the structure —CH═CH—CH═CH—; 
     W is S or O, 
     X is —NR 8 CH 2 —, —NR 8 —, or O; 
     R 8  is hydrogen or alkyl; 
     Y is carbonyl, methylene, ethyl, or —NHCH 2 —; 
     Z is phenyl, pyridyl, naphthyl, thienyl, furyl, pyrrolyl, pyrazolyl, isoxazolyl, or isothiazolyl; 
     or a pharmaceutically acceptable salt thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia.

This application is a continuation of application Ser. No. 09/887,672,filed Apr. 23, 2001 which is a continuation of Ser. No. 09/564,496,filed May 4, 2000, now U.S. Pat. No. 6,248,764, which is a division ofSer. No. 09/307,691, filed May 10, 1999, now U.S. Pat. No. 6,103,708,which claims priority of Provisional Application No. 60/126,416, filedMay 12, 1998, now abandoned.

BACKGROUND OF THE INVENTION

The prevalence of insulin resistance in glucose intolerant subjects haslong been recognized. Reaven et al (American Journal of Medicine 1976,60, 80) used a continuous infusion of glucose and insulin(insulin/glucose clamp technique) and oral glucose tolerance tests todemonstrate that insulin resistance existed in a diverse group ofnonobese, nonketotic subjects. These subjects ranged from borderlineglucose tolerant to overt, fasting hyperglycemia. The diabetic groups inthese studies included both insulin dependent (IDDM) and noninsulindependent (NIDDM) subjects.

Coincident with sustained insulin resistance is the more easilydetermined hyperinsulinemia, which can be measured by accuratedetermination of circulating plasma insulin concentration in the plasmaof subjects. Hyperinsulinemia can be present as a result of insulinresistance, such as is in obese and/or diabetic (NIDDM) subjects and/orglucose intolerant subjects, or in IDDM subjects, as a consequence ofover injection of insulin compared with normal physiological release ofthe hormone by the endocrine pancreas.

The association of hyperinsulinemia with obesity and with ischemicdiseases of the large blood vessels (e.g. atherosclerosis) has been wellestablished by numerous experimental, clinical and epidemiologicalstudies (summarized by Stout, Metabolism 1985, 34, 7, and in more detailby Pyorala et al, Diabetes/Metabolism Reviews 1987, 3, 463).Statistically significant plasma insulin elevations at 1 and 2 hoursafter oral glucose load correlates with an increased risk of coronaryheart disease.

Since most of these studies actually excluded diabetic subjects, datarelating the risk of atherosclerotic diseases to the diabetic conditionare not as numerous, but point in the same direction as for nondiabeticsubjects (Pyorala et al). However, the incidence of atheroscleroticdiseases in morbidity and mortality statistics in the diabeticpopulation exceeds that of the nondiabetic population (Pyorala et al;Jarrett Diabetes/Metabolism Reviews 1989,5, 547; Harris et al, Mortalityfrom diabetes, in Diabetes in America 1985).

The independent risk factors obesity and hypertension foratherosclerotic diseases are also associated with insulin resistance.Using a combination of insulin/glucose clamps, tracer glucose infusionand indirect calorimetry, it has been demonstrated that the insulinresistance of essential hypertension is located in peripheral tissues(principally muscle) and correlates directly with the severity ofhypertension (DeFronzo and Ferrannini, Diabetes Care 1991, 14, 173). Inhypertension of the obese, insulin resistance generateshyperinsulinemia, which is recruited as a mechanism to limit furtherweight gain via thermogenesis, but insulin also increases renal sodiumreabsorption and stimulates the sympathetic nervous system in kidneys,heart, and vasculature, creating hypertension.

It is now appreciated that insulin resistance is usually the result of adefect in the insulin receptor signaling system, at a site post bindingof insulin to the receptor. Accumulated scientific evidencedemonstrating insulin resistance in the major tissues which respond toinsulin (muscle, liver, adipose), strongly suggests that a defect ininsulin signal transduction resides at an early step in this cascade,specifically at the insulin receptor kinase activity, which appears tobe diminished (reviewed by Haring, Diabetalogia 1991, 34, 848).

Protein-tyrosine phosphatases (PTPases) play an important role in theregulation of phosphorylation of proteins. The interaction of insulinwith its receptor leads to phosphorylation of certain tyrosine moleculeswithin the receptor protein, thus activating the receptor kinase.PTPases dephosphorylate the activated insulin receptor, attenuating thetyrosine kinase activity. PTPases can also modulate post-receptorsignaling by catalyzing the dephosphorylation of cellular substrates ofthe insulin receptor kinase. The enzymes that appear most likely toclosely associate with the insulin receptor and therefore, most likelyto regulate the insulin receptor kinase activity, include PTP1B, LAR,PTPα and SH-PTP2 (B. J. Goldstein, J. Cellular Biochemistry 1992, 48,33; B. J. Goldstein, Receptor 1993, 3, 1-15,; F. Ahmad and B. J.Goldstein Biochim. Biophys Acta 1995, 1248, 57-69).

McGuire et al. (Diabetes 1991, 40, 939), demonstrated that nondiabeticglucose intolerant subjects possessed significantly elevated levels ofPTPase activity in muscle tissue vs. normal subjects, and that insulininfusion failed to suppress PTPase activity as it did in insulinsensitive subjects.

Meyerovitch et al (J. Clinical Invest. 1989, 84, 976) observedsignificantly increased PTPase activity in the livers of two rodentmodels of IDDM, the genetically diabetic BB rat, and the STZ-induceddiabetic rat. Sredy et al (Metabolism, 44, 1074, 1995) observed similarincreased PTPase activity in the livers of obese, diabetic ob/ob mice, agenetic rodent model of NIDDM.

The compounds of this invention have been shown to inhibit PTPasesderived from rat liver microsomes and human-derived recombinantPTPase-1B (hPTP-1B) in vitro. They are useful in the treatment ofinsulin resistance associated with obesity, glucose intolerance,diabetes mellitus, hypertension and ischemic diseases of the large andsmall blood vessels.

C. Goldenberg et al., Eur. J. Med. Chem.—Chim. Ther. 1977, 12(1), 81-86and M. Descamps et al., (DE 2710047) disclosed compounds of formula A.

G. J. Cullinan and K. J. Fahey (U.S. Pat. No. 5,596,106 A and WO 960201)disclose arylbenzo[b]thiophene and benzo[b]furan compounds B and C ascannabinoid receptor antagonists.

H. Grote (DE 3342624 A1) disclose Benzarone derivatives D for treatingvenous and arterial ailments.

(R, R¹, R² and R³ is H, alkoxy, acyloxy, OH, SO₃H; R⁴ is H, acyl, HSO₂)

T. Eckert (DE 3110460 and Arch. Pharm. (Weinheim, Ger.) 1982, 315(6),569-570 discloses sodium benzaron sulfate E.

None of the above disclosures (A-E) contained the appropriatesubstitution necessary for in vitro PTPase inhibition activity.

DESCRIPTION OF THE INVENTION

This invention provides a compound of formula I having the structure

wherein

R¹ and R² are each, independently, hydrogen, alkyl of 1-6 carbon atoms,halogen, perfluoroalkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbonatoms, thienyl, furyl, phenyl or phenyl substituted withtrifluoromethyl, chloro, methoxy, or trifluoromethoxy;

R³ and R⁴ are each, independently, hydrogen, carboxy, hydroxy,hydoxyalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms,perfluoroalkoxy of 1-6 carbon atoms, alkanoyloxy of 2-7 carbon atoms,perfluoroalkanoyloxy of 2-7 carbon atoms, arylalkoxy of 7-15 carbonatoms, aryloxy of 6-12 carbon atoms, aroyloxy of 7-13 carbon atoms,aryloxycarbonyl of 7-13 carbon atoms, alkoxycarbonyl of 2-7 carbonatoms, perfluoroalkoxycarbonyl of 2-7 carbon atoms, alkyl of 1-6 carbonatoms, perfluoroalkyl of 1-6 carbon atoms, alkylamino of 1-6 carbonatoms, dialkylamino of 1-6 carbon atoms per alkyl group, tetrazolyl,mercapto, nitrile, nitro, amino, —NHSO₂CF₃, carbamoyl, formyl, halogen,acylamino, 3-hydroxy-cyclobut-3-ene-4-yl-1,2-dione, or tetronic acid;

R⁵ is hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbonatoms, naphthalenylmethyl, benzyl or benzyl substituted with halogen,

R⁶ and R⁷ are each, independently, hydrogen, alkyl of 1-6 carbon atoms,or perfluoroalkyl of 1-6 carbon atoms, or R⁶ and R⁷ may be takentogether as a diene unit having the structure —CH═CH—CH═CH—;

W is S or O,

X is —NR⁸CH₂—, —NR⁸—, or O;

R⁸ is hydrogen or alkyl of 1-6 carbon atoms;

Y is carbonyl, methylene, —CH₂CH₂—, or —NHCH₂—;

Z is phenyl, pyridyl, naphthyl, thienyl, furyl, pyrrolyl, pyrazolyl,isoxazolyl, or isothiazolyl;

or a pharmaceutically acceptable salt thereof, which are useful intreating metabolic disorders related to insulin resistance orhyperglycemia.

Pharmaceutically acceptable salts can be formed from organic andinorganic acids, for example, acetic, propionic, lactic, citric,tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,camphorsulfonic, and similarly known acceptable acids when a compound ofthis invention contains a basic moiety. Salts may also be formed fromorganic and inorganic bases, preferably alkali metal salts, for example,sodium, lithium, or potassium, when a compound of this inventioncontains a carboxylate or phenolic moiety, or similar moiety capable offorming base addition salts.

Alkyl includes both straight chain as well as branched moieties. Halogenmeans bromine, chlorine, fluorine, and iodine. It is preferred that thearyl portion of the aryl, arylkyl, arylalkoxy, aryloxy, aroyloxy, oraryloxycarbonyl substituent is a phenyl, naphthyl or1,4-benzodioxan-5-yl group, with phenyl being most preferred. The arylmoiety may be optionally mono-, di-, or tri- substituted with asubstituent selected from the group consisting of alkyl of 1-6 carbonatoms, alkoxy of 1-6 carbon atoms, trifluoromethyl, halogen,alkoxycarbonyl of 2-7 carbon atoms, alkylamino of 1-6 carbon atoms, anddialkylamino in which each of the alkyl groups is of 1-6 carbon atoms,nitro, cyano, —CO₂H, alkanoyloxy of 2-7 carbon atoms, and alkylcarbonylof 2-7 carbon atoms.

The compounds of this invention may contain an asymmetric carbon atomand some of the compounds of this invention may contain one or moreasymmetric centers and may thus give rise to optical isomers anddiastereomers. While shown without respect to stereochemistry in FormulaI, the present invention includes such optical isomers anddiastereomers, as well as the racemic and resolved, enantiomericallypure R and S stereoisomers, as well as other mixtures of the R and Sstereoisomers and pharmaceutically acceptable salts thereof.

Preferred compounds of this invention are those compounds of Formula I,wherein

R¹ and R² are each, independently, hydrogen, alkyl of 1-6 carbon atoms,halogen, perfluoroalkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbonatoms, thienyl, furyl, phenyl or phenyl substituted withtrifluoromethyl, chloro, methoxy, or trifluoromethoxy;

R³ and R⁴ are each, independently, hydrogen, carboxy, hydroxy, alkoxy of1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, alkanoyloxy of2-7 carbon atoms, perfluoroalkanoyloxy of 2-7 carbon atoms, aroyloxy of7-13 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, aryloxycarbonylof 7-13 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6carbon atoms, tetrazolyl, mercapto, nitrile, amino, —NHSO₂CF₃,carbamoyl, formyl, acylamino of 2-7 carbon atoms;

R⁵ is hydrogen, alkyl of 1-6 carbon atoms, naphthalenylmethyl, benzyl orbenzyl substituted with halogen;

R⁶ and R⁷ are each, independently hydrogen or alkyl of 1-6 carbon atomsor R⁶ and R⁷ may be taken together as a diene unit having the structure—CH═CH—CH═CH—;

W is S or O,

X is —NHCH₂—, or O;

Y is carbonyl, methylene, —CH₂CH₂—, or —NHCH₂—;

Z is phenyl, pyridyl, naphthyl, thienyl, furyl, pyrrolyl, pyrazolyl,isoxazolyl, or isothiazolyl;

or a pharmaceutically acceptable salt thereof.

More preferred compounds of this invention are those compounds ofFormula I, wherein

R¹ and R² are each, independently, hydrogen, iodo, phenyl, thienyl,alkyl of 1-6 carbon atoms, bromo, or cycloalkyl of 3-8 carbon atoms,

R³ and R⁴ are each, independently, hydrogen, carboxy, hydroxy, methyl,or acetoxy;

R⁵ is hydrogen, alkyl of 1-6 carbon atoms, naphthalenylmethyl, benzyl orbenzyl substituted with bromine;

R⁶ and R⁷ are each, independently, hydrogen or methyl, or R⁶ and R⁷ maybe taken together as a diene unit having the structure —CH═CH—CH═CH—;

W is S or O,

X is —NHCH₂—, or O;

Y is carbonyl, methylene, —CH₂CH₂—, —NHCH₂—;

Z is phenyl, or pyrazolyl;

or a pharmaceutically acceptable salt thereof.

Specifically preferred compounds of the present invention are set forthbelow:

4-[2,6-Dibromo-4-(2-ethyl-benzofuran-3-carbonyl)-phenoxysulfonyl]-2-hydroxy-benzoicacid or a pharmaceutically acceptable salt thereof.

4-[5′-(2-Butyl-benzofuran-3-carbonyl)-[1,1′;3′1″]terphenyl-2′-yloxysulfonyl]-2-hydroxy-benzoic acid or apharmaceutically acceptable salt thereof.

4-[4-(2-Ethyl-benzofuran-3-carbonyl)-2,6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoicacid or a pharmaceutically acceptable salt thereof.

4-[4-(2-Ethyl-benzofuran-3-carbonyl)-2,6-diisopropyl-phenoxysulfonyl]-2-hydroxy-benzoicacid or a pharmaceutically acceptable salt thereof.

4-[4-(2-Benzyl-4,5-dimethyl-furan-3-carbonyl)-2,6-diisopropyl-phenoxysulfonyl]-2-hydroxy-benzoicacid or a pharmaceutically acceptable salt thereof.

4-[5′-(2-Ethyl-benzofuran-3-carbonyl)-[1,1′;3′,1″]terphenyl-2′-yloxysulfonyl]-2-hydroxy-benzoicacid or a pharmaceutically acceptable salt thereof.

4-[5-(2-Benzyl-4,5-dimethyl-furan-3-carbonyl)-3-methyl-biphenyl-2-yloxysulfonyl]-2-hydroxy-benzoicacid or a pharmaceutically acceptable salt thereof.

4-[4-(4,5-Dimethyl-2-naphthalen-2-ylmethyl-furan-3-carbonyl)-2,6-diisopropyl-phenoxysulfonyl]-2-hydroxy-benzoicacid or a pharmaceutically acceptable salt thereof.

4-{4-[2-(2-Bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2,6-diisopropyl-phenoxysulfonyl}-2-hydroxy-benzoicacid or a pharmaceutically acceptable salt thereof.

4-{4-[2-(3-Bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2,6-diisopropyl-phenoxysulfonyl}-2-hydroxy-benzoicacid or a pharmaceutically acceptable salt thereof.

4-{4-[2-(4-Bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2,6-diisopropyl-phenoxysulfonyl}-2-hydroxy-benzoicacid or a pharmaceutically acceptable salt thereof.

2-Acetoxy-4-{4-[2-(2-Bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-benzoicacid or a pharmaceutically acceptable salt thereof.

2-Acetoxy-4-{4-[2-(4-Bromo-benzyl)-4,5-dimethyl-thiophene-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-benzoicacid or a pharmaceutically acceptable salt thereof.

2-Acetoxy-4-[4-(2-benzyl-4,5-dimethyl-thiophene-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl-benzoic acid or a pharmaceutically acceptable salt thereof.

2-Acetoxy-4-[4-(2-benzyl-4,5-dimethyl-furan-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl]-benzoicacid or a pharmaceutically acceptable salt thereof.

4-[4-(2-Benzyl-4,5-dimethyl-furan-3-carbonyl)-2,6-diethyl-phenoxysulfonyl]-2-hydroxy-benzoicacid or a pharmaceutically acceptable salt thereof.

1-Methyl-1H-pyrazole-4-sulfonic acid4-[2-(4-bromo-benzyl)4,5-dimethyl-thiophene-3-carbonyl]-2-cyclopentyl-phenylester or a pharmaceutically acceptable salt thereof.

4-{4-[2-(2-Bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-2-hydroxy-benzoicacid or a pharmaceutically acceptable salt thereof.

4-{4-[2-(4-Bromo-benzyl)-4,5-dimethyl-thiophene-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-2-hydroxy-benzoicacid or a pharmaceutically acceptable salt thereof.

4-[4-(2-Benzyl-4,5-dimethyl-thiophene-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl]-2-hydroxy-benzoicacid or a pharmaceutically acceptable salt thereof.

4-[4-(2-Benzyl-4,5-dimethyl-furan-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl]-2-hydroxy-benzoicacid or a pharmaceutically acceptable salt thereof.

4-{4-[2-(4-Bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-2-hydroxy-benzoicacid or a pharmaceutically acceptable salt thereof.

4-[4-(2-Butyl-benzofuran-3-ylmethyl)-phenoxysulfonyl]-2-hydroxy-benzoicacid or a pharmaceutically acceptable salt thereof.

4-[4-(2-Butyl-benzofuran-3-carbonyl)-phenoxysulfonyl]-2-hydroxy-benzoicacid or a pharmaceutically acceptable salt thereof.

4-{4-[2-(2-Butyl-benzofuran-3-yl)-ethyl]-phenoxysulfonyl}-2-hydroxy-benzoicacid or a pharmaceutically acceptable salt thereof.

2-Acetoxy-4-{4-[2-(2-butyl-benzofuran-3-yl)-ethyl]-phenoxysulfonyl}-benzoicacid or a pharmaceutically acceptable salt thereof.

4-{4-[(2-Butyl-benzofuran-3-ylmethyl)-amino]-phenoxysulfonyl}-2-hydroxy-benzoicacid or a pharmaceutically acceptable salt thereof.

4-{4-[2-(2-Benzyl-benzo[b]thiophen-3-yl)-ethyl]-phenoxysulfonyl}-2-hydroxy-benzoic acid or apharmaceutically acceptable salt thereof.

The compounds of this invention were be prepared according to thefollowing schemes from commercially available starting materials orstarting materials which can be prepared using to literature procedures.These schemes show the preparation of representative compounds of thisinvention.

In Scheme 1, 2, 3-dimethylthiophene (II: W is S) is prepared fromcommercially available 3-methyl-thiophene-carboxaldehyde usingWolff-Kishner conditons (hydrazine followed by KOH/ethylene glycolreflux). Compound (II) is treated with one to 1.3 molar equivalents ofan alkyl lithium reagent such as N-butyl lithium most preferably in anonprotic solvent such as THF at temperatures ranging from −78° C. toroom temperature under an inert atmosphere such as nitrogen or argon toprovide the 2-lithiated-thiophene or furan derivative. This lithiatedanalog is reacted in situ with one or more molar equivalents ofbenzaldehyde, generally at −78° C. to room temperature for 5 min to 3 hto provide the compound of formula (III: Q is OH). The hydroxy group of(III: Q is OH) can be removed by a number of reduction procedures suchas hydrogenation using palladium catalysts to produce the compound offormula (III: Q is H) but is most conveniently removed using the methodof Nutaitis, et. al. (Org. Prep. and Proceed. Int. 1991, 23, 403-411) inwhich (III: Q is OH; W is S or O) is stirred with one to ten molarequivalents of sodium borohydride in a suitable solvent such as ether,THF or dichloromethane at 0° C. to room temperature and one to fiftymolar equivalents of trifluoroacetic acid is slowly added over a 15 minto 3 h period to produce the compound of formula (III: Q is H).Alternatively, the 2-lithiated analog of compound (II) in a nonproticsolvent such as THF can be reacted with one or more molar equivalents ofa benzyl halide such as benzyl bromide (PhCH₂Br) at −78° C. to roomtemperature to directly provide the compound of formula (III: Q is H; Wis S or O).

The compounds of formula (III: Q is H) can be acylated with one or moremolar equivalents of a commercially available benzoic acid chloride offormula (IV: X is O-alkyl) to produce the acylated derivative of formula(V: X is O-alkyl). This acylation is accomplished most readily using aone to five molar equivalents of a Lewis acid catalyst such as tintetrachloride or aluminum chloride in an inert solvent such asdichloromethane, 1,2-dichloroethane or carbon disulfide, generally attemperatures such as −78° C. to room temperature. The benzoic acidchloride (IV: X is —O-alkyl). is prepared from the corresponding benzoicacid by standard procedures using reagents such as oxalyl chloride andthionyl chloride. The starting benzoic acid of the benzoic acid chloride(IV: X is O-alkyl) is commercially available or can be easily preparedby known procedures. For example, the acid starting material for benzoicacid chloride (IV) can be prepared using a modification of the method ofSchuster, et al., J. Org. Chem. 1988, 53, 5819. Thus commerciallyavailable 2, 6-diisopropyl phenol is brominated in the 4-position(bromine/acetic acid), methylated (iodomethane/potassium carbonate/DMF),reacted with n-butyl lithium to effect lithium halogen exchange and theresultant organolithium species is reacted with carbon dioxide toprovide 3,5-diisopropyl, 4-methoxy benzoic acid. Alternatively, thecommercially available 2,6-(mono or disubstituted)phenols can bemethylated (iodomethane/potassium carbonate/DMF), acylated in the4-position with 2-chlorobenzoyl chloride in the presence of aluminumchloride in an inert solvent such as dichloromethane, generally atambient temperature and reacted with potassium-t-butoxide inH₂O/ethylene glycol dimethyl ether at ambient temperature to give thedesired 2,6-(mono or disubstituted)benzoic acid.

The conversion of the alkyl ether compound (V: X is O-alkyl) to thephenol compound (Va: X is OH) is generally best accomplished using oneto ten molar equivalents of a strong Lewis acid such as a trihaloborane,most conveniently tribromoborane. The reaction is best performed at −78°C. with warming to 0° C.

The compounds of formula (Va: X is OH) can be sulfonylated on thephenolic oxygen using one or more molar equivalents of suitablesulfonylating agent (VI) to provide the sulfonic acid esters of formula(I: Y is carbonyl). The sulfonylating agent (VI) is generally a aryl orheteroaryl sulfonic acid chloride. The reaction is run under standardconditions using a suitable base such sodium hydride, pyridine or Trisbase in an appropriate solvent such as dichloromethane, THF or H₂O attemperatures from 0° C. to ambient temperature. The starting aryl orheteroaryl sulfonic acid chloride is commercially available or can beeasily prepared by known procedures. The aryl or heteroaryl sulfonicacid chloride can be prepared by reacting the aryl or heteroarylsulfonic acid with one or more molar equivalents of oxalyl chloride orthionyl chloride, in a suitable solvent such as dichloromethane,chloroform or diethyl ether, to afford the aryl or heteroaryl sulfonicacid chloride. This reaction is often catalyzed by adding small amounts(0.01 to 0.1 molar equivalents) of dimethylformamide. Alternatively, thearyl or heteroaryl sulfonic acid chloride can prepared using amodification of Barraclough, et al., Arch. Pharm. (Weinheim) 1990, 323,507. Thus, the aniline of commercially available 4-aminosalicylic acidsodium salt dihydrate is diazotized with sodium nitrite in HOAc/HCl at−10° C. and the subsequent the diazonium salt can converted to thesulfonyl chloride by introduction of sulfur dioxide into the reaction inthe presence of copper (I) chloride.

The groups R³ and R⁴ connected to Z can be further derivatized. Forexample, when R³ or R⁴ is an ester of a carboxylic acid or alcohol thecompound can be transformed into the respective carboxylic acid oralcohol analog using standard conditions. The conditions to effect thesetransformations include aqueous base in which one or more molarequivalents of alkali metal hydroxide such as sodium hydroxide is usedin water with a co-solvent such as THF, dioxane or a lower alcohol suchas methanol or mixtures of THF and a lower alcohol at temperaturesranging from 0° C. to 40° C. When R³ or R⁴ is a carboxylic acid or esterthe compound can be reduced to the respective primary alcohol analogusing standard conditions such as lithium aluminum hydride in ethylether. When R³ or R⁴ is an aldehyde or ketone the compound can bereduced to the respective primary alcohol analog using a metal catalyst,by sodium in alcohol, sodium borohydride and by lithium aluminumhydride. When R³ or R⁴ is an ether, the compound can be transformed tothe free alcohol by using one to ten molar equivalents of a strong Lewisacid such as a trihaloborane, most conveniently tribromoborane in ahalocarbon solvent such as dichloromethane. When R³ or R⁴ is an alcoholthe compound can be oxidized to the respective aldehyde, carboxylic acidor ketone analog using a transition metal oxidant (chromiumtrioxide-pyridine, pyridinium chlorochromate, manganese dioxide) in aninert solvent such as ether, dichloromethane. Alcohols can also beoxidized using DMSO with a number of electrophilic molecules(dicyclohexylcarbodiimide, acetic anhydride, trifluoro acetic anhydride,oxalyl chloride and sulfur dioxide). When R³ or R⁴ is a carboxylic acidthe compound can be transformed into a carboxylic acid amide analog.This transformation can be accomplished using standard methods to effectcarboxylic acid to carboxylic acid amide transformations. These methodsinclude converting the acid to an activated acid and reacting with oneor more molar equivalents of the desired amine. Amines in this categoryinclude ammonia in the form of ammonium hydroxide, hydroxyl amine and2-aminopropionitrile. Methods to activate the carboxylic acid includereacting said acid with one or more molar equivalents of oxalyl chlorideor thionyl chloride to afford the carboxylic acid chloride in a suitablesolvent such as dichloromethane, chloroform or diethyl ether. Thisreaction is often catalyzed by adding small amounts (0.01 to 0.1 molarequivalents) of dimethylformamide. Other methods to activate thecarboxylic acid include reacting said acid with one or more molarequivalents dicyclohexylcarbodiimide with or without one or more molarequivalents of hydroxybenzotriazole in a suitable solvent such asdichloromethane or dimethylformamide at temperatures ranging from 0° C.to 60° C. When R³ or R⁴ is nitro, the compound can be reduced to therespective amino compound most readily using tin dichloride inethylacetate at 40 to 100° C. or with hydrazine and Montmorillinite clayin ethanol at 40 to 100° C. or by catalytic hydrogenation in thepresence of a catalyst such as palladium on carbon. When R³ or R⁴ is anamino or an alcohol, the compound can be acylated using one or moremolar equivalents of suitable acylating agent. The acylating agent isgenerally a lower alkyl or aryl carboxylic acid anhydride or a loweralkyl or aryl carboxylic acid chloride. The reaction is run understandard conditions, for example the use of pyridine as solvent with orwithout a co-solvent such as dichloromethane at 0° C. to roomtemperature. When R³ or R⁴ is an alcohol it can be acylated with a loweralkyl or aryl carboxylic acid anhydride in the presence of magnesiumiodide in diethyl ether at ambient temperature to reflux. When R³ or R⁴is a nitrile it can be reduced to the aminoalkyl compound by tin (II)chloride in refluxing ethyl acetate or by catalytic hydrogenation in thepresence of a catalyst such as Raney nickel or by lithium aluminumhydride in an inert solvent such as ether. When R³ or R⁴ is a nitrile itcan be converted to a carboxylic acid amide using standard conditionssuch as HCl/H₂O at ambient temperatures to reflux or a milder procedureinvolves the reaction of the nitrile with an alkaline solution ofhydrogen peroxide. When R³ or R⁴ is halogen or trifluoromethanesulfonateit can be converted to a 3-hydroxy-cyclobut-3-ene-4-yl-1,2-dione bymethodology of Liebeskind et. al. (J. Org. Chem. 1990, 55, 5359). WhenR³ or R⁴ is an alcohol can be alkylated with a suitable alkylating agentsuch as one or more molar equivalents of alkyl halide in the presence abase such as potassium carbonate or sodium hydroxide in a suitablesolvent such as THF, DMF or DMSO at temperatures ranging from 0° C. to60° C. When R³ or R⁴ is a carboxylic acid, the compound can be coupledto tetronic acid with a coupling reagent such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in the presence of a basesuch as triethylamine or DMAP in a suitable solvent such as DMF.

The following method will prepare derivatives of formula (V: Y ismethylene) that can utilized in Scheme 1 to prepare compounds of formula(I: Y is methylene). The ketone (V: Y is carbonyl) can be reduced withlithium aluminum hydride in an aprotic solvent such as THF at ambienttemperature to give the alcohol (VII). Further reduction of alcohol(VII) with triethylsilane in the presence of boron trifluoride diethyletherate provides the methylene compound (V: Y is methylene). Thecompounds prepared in Scheme 2 of formula (V: Y is methylene) can befurther modified synthetically in Scheme 5.

Derivatives of formula (IV: R¹ and/or R² is H; I; Br; aryl; heteroaryl;X is O-alkyl) can be prepared according to Scheme 3. Thep-hydroxybenzaldehyde (VIII) can be conveniently iodinated to thediiodophenol of formula (VIIIa: R¹ and R² is I) using at least two molarequivalents of iodine in the presence of two or more molar equivalentsof an alkali metal hydroxide such as NaOH in an alcohol solvent such asmethanol at −20° C. to room temperature. Similarly the monoiodophenol(VIIIa: R¹ is H; R² is I) can be prepared from the phenol of formula(VIII) using one to 1.5 molar equivalents of iodine in the presence ofat least one equivalent of an alkali metal hydroxide such as NaOH in aalcohol solvent such as methanol at −20° C. to room temperature. Eitherthe monoiodophenol (VIIIa: R¹ is H; R² is I) or the diiodophenol (VIIIa:R¹ and R² is I) can be converted to the respective alkyl etherderivatives of formula (VIIIb: R¹ is H; R² is I; X is —O-alkyl) or(VIIIb: R¹ and R² is I; X is —O-alkyl) by reacting the phenol moietywith a suitable alkylating agent such as one or more molar equivalentsof methyl iodide or dimethylsulfate employing a base such an alkalimethyl carbonate or hydroxide such as potassium carbonate or sodiumhydroxide in a suitable solvent such as THF, DMF or DMSO. The reactionis generally performed at temperatures ranging from 0° C. to 60° C. Themono or dibrominated benzaldehydes of formula (VIIIb: R¹ and/or R²is Br;X is —O-alkyl) can be prepared in analogs fashion by substitutingbromine for iodine in the sequence above.

The mono or diiodo alkyl ether benzaldehydes of formula (VIIIb: R¹and/or R² is I; X is O-alkyl) can be reacted with an arylboronic acid orheteroarylboronic acid to afford the product of formula (VIIIc: R¹and/or R² is aryl or heteroaryl; X is —O-alkyl) under the conditions ofthe Suzuki Reaction (Journal of the Chemical Society ChemicalCommunications 1979 886 and Synthetic Communications 1981 11(7) 513).The other co-reagents necessary to effect the Suzuki Reaction includeone or more molar equivalents of a metal catalyst such astetrakis(triphenylphosphine)palladium or palladium (II) acetate and abase such as barium hydroxide octahydrate or sodium carbonate in asolvent such as benzene, toluene or DME/H₂O. The starting aryl orheteroaryl boronic acids are commercially available or can be preparedby standard synthetic methods.

The mono or diaryl or mono or diheteroaryl benzaldehyde analogs offormula (VIIIc: R¹ and/or R² is aryl or heteroaryl; X is —O-alkyl) canbe converted to the corresponding mono or diaryl or mono or diheteroarylbenzoic acid analogs of formula (VIIId: R¹ and/or R² is aryl orheteroaryl; X is —O-alkyl) using the oxidative conditions of silver (I)oxide in an aqueous base such as sodium hydroxide at temperaturesranging from 50° C. to reflux.

The benzoic acid compound (VIIId: R¹ and/or R² is H; I; Br; aryl;heteroaryl; X is O-alkyl) can be converted to the corresponding benzoicacid chloride (IV: R¹ and/or R² is H; I; Br; aryl heteroaryl; X isO-alkyl) by standard procedures using reagents such as oxalyl chlorideand thionyl chloride. The compounds prepared in Scheme 3 of formula (IV:R¹ and/or R² is H; I; Br; aryl; heteroaryl; X is O-alkyl) can beutilized in Scheme 1 to prepared compounds of formula (I: R¹ and/or R²is H; I; Br; aryl; heteroaryl).

In an analogous synthetic sequence to Scheme 3, compounds of formula(Va: X is OH; R¹ and/or R² is H) can be functionalized at positions R¹and R² to give compounds of formula (V: X is O-alkyl; R¹ and/or R² is H;I; Br; aryl; heteroaryl). The compounds prepared in Scheme 4 of formula(V: R¹ and/or R² is H; I; Br; aryl; heteroaryl; X is O-alkyl) can beutilized in Scheme 1 to prepared compounds of formula (I: R¹ and/or R²is H; I; Br; aryl; heteroaryl). The compounds prepared in Scheme 4 offormula (V: R¹ and/or R² is H; I; Br; aryl; heteroaryl; X is O-alkyl)can be synthetically modified in Scheme 5.

In a three step process (Scheme 5) compounds of formula (Va: X is OH)can be converted to compounds of formula (Vb: X is —CH₂NH₂). Reaction ofcompounds of formula (Va: X is OH) with trifluoromethanesulfonicanhydride or trifluoromethanesulfonic acid chloride in the presence of aorganic base such as pyridine or triethylamine in dichloromethane at 0°C. to ambient temperature provides compound (IX). The triflate (IX) canbe converted to the carbonitrile (X) with potassium cyanide or zinccyanide in the presence of tetrakistriphenylphosphinenickel(0) which canbe generated in situ from bistriphenylphosphinenickel (II) bromide andZn/PPh₃. The nitrile (X) can be reduced to the aminoalkyl compound (Vb:X is —CH₂NH₂) by tin (II) chloride in refluxing ethyl acetate or bycatalytic hydrogenation in the presence of a catalyst such as Raneynickel or by lithium aluminum hydride in an inert solvent such as ether.

From Scheme 5, the prepared compounds of formula (Vb: X is —CH₂NH₂) canbe used in Scheme 1 to prepared sulfonamides of formula (I: X is—CH₂NH—).

In Scheme 6, the aldehyde (XI) can be prepared from commerciallyavailable furan (III: W is O ) using phosphorus oxychloride in dimethylformaldehyde at 85° C. under an inert atmosphere. Compound (XI) istreated with one to 1.3 molar equivalents of an suitable Wittig reagentin a nonprotic solvent such as THF at temperatures ranging from −78° C.to room temperature under an inert atmosphere such as nitrogen or argonto provide the olefin derivative. The olefin (Vc: Y is —CH═CH—) can beconverted to the alkane (Vd: Y is —CH2CH2—) through any standardprocedure for hydrogenation. The most convenient method of reduction iscatalytic hydrogenation employing 10% palladium on carbon over anatmosphere of hydrogen for 12-24 hours.

The compounds prepared in Scheme 6 of formula (Vc: Y is —CH═CH—) or (Vd:Y is —CH2CH2—) can be utilized in Scheme 1 to prepared compounds offormula (I: Y is —CH═CH— or —CH2CH2—). The compounds prepared in Scheme6 can be synthetically modified in Schemes 4 and 5.

Compounds of formula (Ve: Y is —NHCH2—) in Scheme 7 can be preparedthrough a number of reductive amination procedures such as the method ofMaryanoff, et. al. (J. Org. Chem. 1996, 61, 3849-62), but is easilyprepared by a modified procedure of Borch, et. al. (J. Am. Chem. Soc.1971, 93, 2897-04. A solution of the aldehyde (XI) (as prepared inScheme 6), and the appropriate aniline hydrochloride (XIII) (1.2-1.5equivalent) in a suitable protic solvent such as methanol is stirred atroom temperature in the presence of sodium cyanoborohydride (1.1-1.5equivalent) yields compounds of formula (Ve: Y is —NHCH2—).

The compounds prepared in Scheme 7 of formula (Ve: Y is —NHCH2—) can beutilized in Scheme 1 to prepared compounds of formula (I: Y is —NHCH2—).The compounds prepared in Scheme 6 can be synthetically modified inSchemes 4 and 5.

The compounds of this invention are useful in treating metabolicdisorders related to insulin resistance or hyperglycemia, typicallyassociated with obesity or glucose intolerance. The compounds of thisinvention are therefore, particularly useful in the treatment orinhibition of type II diabetes. The compounds of this invention are alsouseful in modulating glucose levels in disorders such as type Idiabetes.

The ability of compounds of this invention to treat or inhibit disordersrelated to insulin resistance or hyperglycemia was established withrepresentative compounds of this invention in the following standardpharmacological test procedure which measures the inhibition of PTPase.

Inhibition of Tri-Phosphorylated Insulin Receptor DodecaphosphopeptideDephosphorylation by hPTP1B

This standard pharmacological test procedure assess the inhibition ofrecombinant rat protein tyrosine phosphatase, PTP1B, activity using, assubstrate, the phosphotyrosyl dodecapeptide corresponding to the1142-1153 insulin receptor kinase domain, phosphorylated on the 1146,1150 and 1151 tyrosine residues. The procedure used and results obtainedare briefly described below.

Human recombinant PTP1B was prepared as described by Goldstein (seeGoldstein et al. Mol. Cell. Biochem. 109, 107, 1992). The enzymepreparation used was in microtubes containing 500-700 μg/ml protein in33 mM Tris-HCl, 2 mM EDTA, 10% glycerol and 10 mM 2-mercaptoethanol.

Measurement of PTPase Activity

The malachite green-ammonium molybdate method, as described (Lanzetta etal. Anal. Biochem. 100, 95, 1979) and adapted for a platereader, is usedfor the nanomolar detection of liberated phosphate by recombinant PTP1B.The test procedure uses, as substrate, a dodecaphosphopeptide customsynthesized by AnaSpec, Inc. (San Jose, Calif.). the peptide,TRDIYETDYYRK, corresponding to the 1142-1153 catalytic domain of theinsulin receptor, is tyrosine phosphorylated on the 1146, 1150, and 1151tyrosine residues. The recombinant rPTP1B is diluted with buffer (pH7.4, containing 33 mM Tris-HCl, 2 mM EDTA and 50 mM b-mercaptoethanol)to obtain an approximate activity of 1000-2000 nmoles/min/mg protein.The diluted enzyme (83.25 mL) is preincubated for 10 min at 37° C. withor without test compound (6.25 mL) and 305.5 mL of the 81.83 mM HEPESreaction buffer, pH 7.4 peptide substrate, 10.5 ml at a finalconcentration of 50 mM, and is equilibrated to 37° C. in a LABLINEMulti-Blok heater equipped with a titerplate adapter. The preincubatedrecombinant enzyme preparation (39.5 ml) with or without drug is addedto initiate the dephosphorylation reaction, which proceeds at 37° C. for30 min. The reaction is terminated by the addition of 200 mL of themalachite green-ammonium molybdate-Tween 20 stopping reagent (MG/AM/Tw).The stopping reagent consists of 3 parts 0.45% malachite greenhydrochloride, 1 part 4.2% ammonium molybdate tetrahydrate in 4 N HCland 0.5% Tween 20. Sample blanks are prepared by the addition of 200 mLMG/AM/Tw to substrate and followed by 39.5 ml of the preincubatedrecombinant enzyme with or without drug. The color is allowed to developat room temperature for 30 min. and the sample absorbances aredetermined at 650 nm using a platereader (Molecular Devices). Sample andblanks are prepared in quadruplicates.

Calculations

PTPase activities, based on a potassium phosphate standard curve, areexpressed as nmoles of phosphate released/min/mg protein. Inhibition ofrecombinant PTP1B by test compounds is calculated as percent ofphosphatase control. A four parameter non-linear logistic regression ofPTPase activities using SAS release 6.08, PROC NLIN, is used fordetermining IC₅₀ values of test compounds. The following results wereobtained.

Example IC50 (μM)  1 0.251  2 0.130  3 0.421  4 0.559  5 0.083  6 0.256 7 0.180  8 0.075  9 0.083 10 0.226 11 0.099 12 0.183 13 0.267 14 0.06015 28.78% inhibition @ 1.0 μM 16 22.81% inhibition @ 0.5 μM 17 0.643 180.404 19 0.633 20 0.148 21 0.371 22 0.508 23 0.439 24 0.254 25 0.241 2651.37% inhibition @ 1.0 μM 27 22.69% inhibition @ 1.0 μM 28 0.577Phenylarsine oxide 39.7 (reference standard) Sodium orthovanadate 244.8(reference standard) Ammonium molybdate 8.7 tetrahydrate (referencestandard)

Based on the results obtained in the standard pharmacological testprocedure, representative compounds of this invention have been shown toinhibit PTPase activity and are therefore useful in treating metabolicdisorders related to insulin resistance or hyperglycemia, typicallyassociated with obesity or glucose intolerance. More particularly, thecompounds of this invention useful in the treatment or inhibition oftype II diabetes, and in modulating glucose levels in disorders such astype I diabetes. As used herein, the term modulating means maintainingglucose levels within clinically normal ranges.

Effective administration of these compounds may be given at a dailydosage of from about 1 mg/kg to about 250 mg/kg, and may given in asingle dose or in two or more divided doses. Such doses may beadministered in any manner useful in directing the active compoundsherein to the recipient's bloodstream, including orally, via implants,parenterally (including intravenous, intraperitoneal and subcutaneousinjections), rectally, vaginally, and transdermally. For the purposes ofthis disclosure, transdermal administrations are understood to includeall administrations across the surface of the body and the inner liningsof bodily passages including epithelial and mucosal tissues. Suchadministrations may be carried out using the present compounds, orpharmaceutically acceptable salts thereof, in lotions, creams, foams,patches, suspensions, solutions, and suppositories (rectal and vaginal).

Oral formulations containing the active compounds of this invention maycomprise any conventionally used oral forms, including tablets,capsules, buccal forms, troches, lozenges and oral liquids, suspensionsor solutions. Capsules may contain mixtures of the active compound(s)with inert fillers and/or diluents such as the pharmaceuticallyacceptable starches (e.g. corn, potato or tapioca starch), sugars,artificial sweetening agents, powdered celluloses, such as crystallineand microcrystalline celluloses, flours, gelatins, gums, etc. Usefultablet formulations may be made by conventional compression, wetgranulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants,suspending or stabilizing agents, including, but not limited to,magnesium stearate, stearic acid, talc, sodium lauryl sulfate,microcrystalline cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, , xanthan gum,sodium citrate, complex silicates, calcium carbonate, glycine, dextrin,sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose,kaolin, mannitol, sodium chloride, talc, dry starches and powderedsugar. Oral formulations herein may utilize standard delay or timerelease formulations to alter the absorption of the active compound(s).Suppository formulations may be made from traditional materials,including cocoa butter, with or without the addition of waxes to alterthe suppository's melting point, and glycerin. Water soluble suppositorybases, such as polyethylene glycols of various molecular weights, mayalso be used.

It is understood that the dosage, regimen and mode of administration ofthese compounds will vary according to the malady and the individualbeing treated and will be subject to the judgment of the medicalpractitioner involved. It is preferred that the administration of one ormore of the compounds herein begin at a low dose and be increased untilthe desired effects are achieved.

The following procedures describe the preparation of representativeexamples of this invention.

EXAMPLE 1

4-[2,6-Dibromo-4-(2-ethyl-benzofuran-3-carbonyl)-phenoxysulfonyl]-2-hydroxy-benzoicAcid

Step 1

4-Chlorosulphonyl-2-hydroxybenzoic Acid

At ambient temperature, to a stirred solution of commercial4-aminosalicylic acid sodium salt dihydrate (50.25 g, 0.2379 mol) in H₂O(119 mL) was added a solution of 10% aq. NaOH (3.40 mL) and sodiumnitrite (18.06 g, 0.2617 mol) in H₂O (44 mL). This solution was added toa vigorously stirred mixture of conc. HCL (153 mL) and glacial HOAc (76mL) while maintaining the reaction temperature at −10° C. After 5 min.,the dark orange suspension was added to a vigorously stirred mixture ofcopper (I) chloride (2.355 g, 0.02379 mol) in HOAc (128 mL) which hadbeen previously cooled to 0° C. The reaction was saturated with sulfurdioxide for 0.5h. The ice bath was removed and the reaction was stirredfor 18 h. The reaction was quenched into crushed ice (2 L), allowed towarm to ambient temperature and filtered. The crude product was slurriedin 20% THF/ether (1L), dried (MgSO₄), filtered and concentrated to give36.32 g (64%) of the title compound as a red solid, mp 170-185° C.; ¹HNMR (DMSO-d6) δ 7.11-7.16 (m, 2H), 7.76 (d, 1H), 13.2-14.4 (br. s, 2H).

Step 2

4-[2,6-Dibromo-4-(2-ethyl-benzofuran-3-carbonyl)-phenoxysulfonyl]-2-hydroxy-benzoicAcid

At ambient temperature, to a stirred solution of commercialbenzbromarone (0.243 g, 0.574 mmol) in 0.5M aq. NaHCO₃:THF (8 mL; 1:1)was added portionwise 4-chlorosulphonyl-2-hydroxybenzoic acid (0.271 g,1.15 mmol) while maintaining the pH at 8 with the simultaneous additionof 0.5M aq. NaHCO₃. After the addition was complete the reaction wasstirred for 18 h. To the reaction was added4-chlorosulphonyl-2-hydroxybenzoic acid (0.271 g, 1.15 mmol) whilemaintaining the pH at 8 with the simultaneous addition of 0.5M aq.NaHCO₃. After 2 h, the reaction was quenched with 2N HCl (25 mL),extracted with EtOAc and concentrated. The crude product was purified bypreparative HPLC (C18, eluting with 75% CH₃CN/H2O containing 0.1% TFA)and crystallized from EtOAc/hexane to give 0.14 g (39%) of the titlecompound as a white solid, mp 173° C.; ¹H NMR (DMSO-d6) δ 1.25 (t, 3H),2.76 (q, 2H), 7.30 (dt, 1H), 7.36 (dt, 1H), 7.44-7.49 (m, 3H), 7.66 (d,1H), 8.03 (d, 1H), 8.08 (s, 2H). IR (KBr) 3400, 2950, 1680, 1650, 1400and 1180 cm⁻¹. mass spectrum (−ESI), m/z 621/623/625 (M−H). Anal. Calcd.for C₂₄H₁₆Br₂O₈S: C, 46.18; H, 2.58; N, 0.00. Found: C, 46.41; H, 2.64;N, 0.00.

EXAMPLE 2

4-[5′-(2-Butyl-benzofuran-3-carbonyl)-[1,1′;3′1″]terphenyl-2′-yloxysulfonyl]-2-hydroxy-benzoic acid

Step 1

2-n-Butyl-3-(4-hydroxy-3,5-diiodobenzoyl)benzofuran

At 0° C., to a stirred solution containing commercial2-n-butyl-3-(4-hydroxybenzoyl)benzofuran (1.05 g, 3.57 mmol) and sodiumhydroxide (0.286 g, 7.14 mmol) in MeOH (35.7 mL) was added iodine (2.27g, 8.93 mmol). After 24 h, the reaction was quenched with 1N HCl (30 mL)and extracted with ether. The combined ethereal extracts were washedwith 10% aq. Na₂S₂O₃ (3×), with brine (3×), dried (MgSO₄) andconcentrated. The crude product was purified on Biotage KP-Sil to give0.914 g (47%) of the title compound. ¹H NMR (DMSO-d6) δ 0.85 (t, 3H),1.27 (sextet, 2H), 1.71 (quintet, 2H), 2.77 (t, 2H), 7.29-7.36 (m, 2H),7.45 (d, 1H), 7.65 (d, 1H), 8.11 (s, 2H), 10.5 (br s, 1H).

Step 2

2-n-Butyl-3-(4-[(2-methoxyethoxy)methoxy]-3,5-diiodobenzoyl)benzofuran

At 0° C., to a stirred solution of2-n-butyl-3-(4-hydroxy-3,5-diiodobenzoyl)benzofuran (0.897 g, 1.64 mmol)in THF (16.4 mL) was added 60% NaH/mineral oil (85.4 mg, 2.14 mmol).After 0.5 h, to the reaction was added MEM chloride (0.301 mL, 2.63mmol) and the reaction was stirred for 18 h eventually warming toambient temperature. The reaction was quenched with 1N NaOH (30 mL) andextracted with ether. The ethereal extracts were washed with 1N NaOH(3×), with brine (3×), dried (K₂CO₃) and concentrated to give 1.042 g(100%) of the title compound. ¹H NMR (DMSO-d6) δ 0.85 (t, 3H), 1.26(sextet, 2H), 1.70 (quintet, 2H), 2.74 (t, 2H), 3.28 (s, 3H), 3.56 (t,2H), 4.03 (t, 2H), 5.26 (s, 2H), 7.28-7.40 (m, 2H), 7.49 (d, 1H), 7.66(d, 1H), 8.18 (s, 2H).

Step 3

(2-n-Butyl-benzofuran-3-yl)-(2′-[(2-methoxyethoxy)methoxy]-[1,1′;3′,1″]terphenyl-5′-yl)-methanone

At ambient temperature, to a stirred mixture containing phenylboronicacid (0.454 g, 3.73 mmol), barium hydroxide octahydrate (1.60 g, 5.08mmol) and palladium (II) acetate (7.60 mg, 0.0339 mmol) in DME:H₂O (6:1,20 mL) was added a solution of2-n-butyl-3-(4-[(2-methoxyethoxy)methoxy]-3,5-diiodobenzoyl)benzofuran(1.07 g, 1.69 mmol) in DME:H₂O (6:1, 20 mL). After the addition wascomplete, the reaction was heated at 80° C. for 16 h. The reaction wascooled to ambient temperature, diluted with ether (50 mL), washedsequentially with sat. aq. NaHCO₃ (3×), with brine (3×), dried (MgSO₄)and concentrated. The crude product was purified on Biotage KP-Sileluting with 25% ether/pet. ether to give 0.380 g (42%) of the titlecompound. ¹H NMR (DMSO-d6) δ 0.76 (t, 3H), 1.22 (sextet, 2H), 1.64(quintet, 2H), 2.81-2.92 (m, 6H), 3.03 (s, 3H), 4.44 (s, 2H), 7.31-7.67(m, 14H), 7.76 (s, 2H).

Step 4

(2-n-Butyl-benzofuran-3-yl)-(2′-hydroxy-[1,1′;3′,1″]terphenyl-5′-yl)-methanone

At ambient temperature, to a stirred solution of(2-n-butyl-benzofuran-3-yl)-(2′-[(2-methoxyethoxy)methoxy]-[1,1′;3′,1″]terphenyl-5′-yl)-methanone(0.371 g, 0.695 mmol) in CH₂Cl₂ (3.71 mL) was added trifluoroacetic acid(3.71 mL). After 0.5 h, the reaction was diluted with ether (50 mL),washed with H₂O (3×), dried (MgSO₄) and concentrated. The crude productwas purified on Biotage KP-Sil eluting with 10% acetone/hexane to give0.281 g (90%) of the title compound. ¹H NMR (DMSO-d6) δ 0.77 (t, 3H),1.22 (sextet, 2H), 1.64 (quintet, 2H), 2.87 (t, 2H), 7.29-7.65 (m, 14H),7.66 (s, 2H), 9.39 (s, 1H).

Step 5

4-[5′-(2-Butyl-benzofuran-3-carbonyl)-[1,1′;3′1″]terphenyl-2′-yloxysulfonyl]-2-hydroxy-benzoic Acid

The title compound was prepared according to the procedure in Example 1,step 2, using(2-n-butyl-benzofuran-3-yl)-(2′-hydroxy-[1,1′;3′,1″]terphenyl-5′-yl)-methanone(0.136 g, 0.305 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.144g, 6.09 mmol) to give 0.080 g (38%) of the title compound as a whitesolid, mp 190-197° C.; ¹H NMR (DMSO-d6) δ 0.77 (t, 3H), 1.22 (sextet,2H), 1.63 (quintet, 2H), 2.83 (t, 2H), 6.55 (d, 1H), 6.66 (dd, 1H),7.28-7.38 (m, 8H), 7.41-7.43 (m, 4H), 7.51 (dd, 1H), 7.57 (d, 1H), 7.64(d, 1H), 7.74 (s, 2H). IR (KBr) 2900, 1675, 1390 and 1190 cm⁻¹. massspectrum (−ESI), m/z 645 (M−H). Anal. Calcd. for C₃₈H₃₀O₈S.2H₂O:C,66.85;H, 5.02; N, 0.00. Found: C, 66.80; H, 4.88; N, 0.07.

EXAMPLE 3

4-[4-(2-Ethyl-benzofuran-3-carbonyl)-2,6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoicAcid

The title compound was prepared according to the procedure in Example 1,step 2, using 2-n-ethyl-3-(4-hydroxy-3,5-dimethylbenzoyl)benzofuran(0.250 g, 0.849 mmol, RN 52489-58-4) and4-chlorosulphonyl-2-hydroxybenzoic acid (0.402 g, 1.70 mmol) to give0.15 g (36%) of the title compound as a white solid, mp 166-167° C.; ¹HNMR (DMSO-d6) δ 1.24 (t, 3H), 2.14 (s, 6H), 2.74 (q, 2H), 7.30 (dt, 1H),7.36 (dt, 1H), 7.44-7.48 (m, 3H), 7.57 (s, 2H), 7.66 (d, 1H), 8.05 (d,1H). IR (KBr) 3400, 2950, 1680, 1650 and 1180 cm⁻¹. mass spectrum(−ESI), m/z 493 (M−H). Anal. Calcd. for C₂₆H₂₂O₈S.0.4H₂O: C, 62.24; H,4.58; N, 0.00. Found: C, 62.16; H, 4.53; N, 0.10.

EXAMPLE 4

4-[4-(2-Ethyl-benzofuran-3-carbonyl)-2,6-diisopropyl-phenoxysulfonyl]-2-hydroxy-benzoicAcid

At 5° C., to a stirred suspension containing2-n-ethyl-3-(4-hydroxy-3,5-diisopropylbenzoyl)benzofuran (0.300 g, 0.856mmol, RN 52901-28-7) and 0.05 M Tris buffer pH 9 (3.41 mL) in THF (1.03mL) was added dropwise, a solution of 4-chlorosulphonyl-2-hydroxybenzoicacid (0.243 g, 1.03 mmol) in THF (2.05 mL) while maintaining the pH at10 with the simultaneous addition of 2N NaOH. After the addition wascomplete, the reaction was stirred for 1.5 h. To the reaction was added4-chlorosulphonyl-2-hydroxybenzoic acid (0.243 g, 1.03 mmol) in THF(2.05 mL) while maintaining the pH at 10 with the simultaneous additionof 2N NaOH. and the reaction was stirred for 1.5 h. The reaction wasquenched with 2N HCl (40 mL) and extracted with EtOAc. The combinedorganic extracts were washed with 2N HCl (3×), dried (MgSO₄) andconcentrated. The crude product was purified by preparative HPLC (C18,eluting with 75% CH₃CN/H₂O containing 0.1% TFA) to give 0.30 g (64%) ofthe title compound as a white solid, mp 200-201° C.; ¹H NMR (DMSO-d6) δ1.05 (d, 12H), 1.24 (t, 3H), 2.80 (q, 2H), 3.09 (septet, 2H), 7.26 (dt,1H), 7.32-7.36 (m, 2H), 7.45 (d, 1H), 7.49 (dd, 1H), 7.62 (s, 2H),7.64-7.66 (m, 1H), 8.06 (d, 1H). IR (KBr) 3400, 2950, 1680, 1620, 1490and 1190 cm⁻¹. mass spectrum (EI), m/z 550 (M+). Anal. Calcd. forC₃₀H₃₀O₈S.0.8H₂O: C, 63.77; H, 5.64; N, 0.00. Found: C, 63.81; H, 5.55;N, 0.10.

EXAMPLE 5

4-[4-(2-Benzyl-4,5-dimethyl-furan-3-carbonyl)-2.6-diisopropyl-phenoxysulfonyl]-2-hydroxy-benzoicAcid

Step 1

2-Benzyl-4,5-dimethylfuran

At −78° C., to a stirred solution of commercial 2,3-dimethylfuran (50 g,0.520 mol) in THF (2.6 L) was add dropwise 1.6M n-BuLi/hexanes (325 mL,0.520 mol). After the addition was complete, the dry ice/acetone bathwas removed and the reaction was stirred for 1 h. At −78° C., to thereaction was added dropwise commercial benzyl bromide (62 mL, 0.520mol). After the addition was complete the reaction was stirred at −78°C. for 6 h, the dry ice/acetone bath was removed and the reaction wasstirred for 7 days. The reaction was concentrated in vacuo and purifiedon silica gel eluting with hexane to give 75.70 g (78%) of the titlecompound as a clear oil; ¹H NMR (DMSO-d6) δ 1.83 (s, 3H), 2.08 (s, 3H),3.83 (s, 2H), 5.83 (s, 1H), 7.16-7.30 (m, 5H). mass spectrum (EI), m/z186 (M+).

Step 2

(2-Benzyl-4,5-dimethyl-furan-3-yl)-(3,5-diisopropyl-4-methoxy-phenyl)-methanone

At ambient temperature, to a stirred suspension containing3,5-diisopropyl-p-anisic acid (1.95 g, 8.23 mmol, RN-117439-59-5) andoxalyl chloride (0.8 mL, 9.20 mmol) in CH₂Cl₂ (22.5 mL) was addedN,N-dimethylformamide (2 drops). After 2 h, the reaction was cooled to−78° C. To the reaction was added tin (IV) chloride (1.05 mL) followedby a solution of 2-benzyl-4,5-dimethylfuran (1.8 g, 9.68 mmol) in CH₂Cl₂(10.0 mL). After the additions were complete, the reaction was allowedto warm to ambient temperature and stirred for 24 h. The reaction wasquenched into crushed ice (100 g), diluted with sat. aq. KH₂PO₄ (100 mL)and extracted with ether. The combined ethereal extracts were washedwith sat aq. NaHCO₃ (2×60 mL), with brine (1×60 mL), dried (Na₂SO₄) andconcentrated. The crude product was purified on Biotage KP-Sil elutingwith 1% EtOAc/pet. ether to give 2.07 g, (62%) of the title compound asan oil; ¹H NMR (DMSO-d6) δ 1.17 (d, 12H), 1.81 (s, 3H), 2.19 (s, 3H),3.29 (septet, 2H), 3.74 (s, 3H), 3.84 (s, 2H), 7.01-7.03 (m, 2H),7.16-7.25 (m, 3H), 7.47 (s, 2H). mass spectrum (EI), m/z 404 (M+). Anal.Calcd. for C₂₇H₃₂O_(3.)0.6H₂O: C, 78.07; H, 8.06; N, 0.00. Found: C,78.04; H, 7.93; N, −0.02.

Step 3

(2-Benzyl-4,5-dimethyl-furan-3-yl)-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone

At −78° C., to a stirred solution of(2-benzyl-4,5-dimethyl-furan-3-yl)-(3,5-diisopropyl-4-methoxy-phenyl)-methanone(2.00 g, 4.94 mmol) in CH₂Cl₂ (16.6 mL) was added 1M borontribromide/CH₂Cl₂ (10.4 mL). After the addition was complete, the dryice/acetone bath was replaced with an ice bath and the reaction wasstirred for 1.5 h. The reaction was quenched into crushed ice (18 g),diluted with H₂O (20 mL) and extracted with ether. The combined etherealextracts were washed with brine, dried (MgSO₄) and concentrated. Thecrude product was purified on silica gel eluting with 15% acetone/hexaneto give 0.97 g (50%) of the title compound as a white solid, mp 138° C.;¹H NMR (DMSO-d6) δ 1.14 (d, 12H), 1.80 (s, 3H), 2.19 (s, 3H), 3.34[septet (under H₂O peak), 2H], 3.84 (s, 2H), 7.04 (d, 2H), 7.17-7.25 (m,3H), 7.44 (s, 2H), 9.11 (s, 1H). IR (KBr) 3400, 2950, 1580, 1320, 1200cm⁻¹. mass spectrum (EI), m/z 390 (M+). Anal. Calcd. forC₂₆H₃₀O₃.0.2H₂O: C, 79.24; H, 7.77; N, 0.12. Found: C, 79.27; H, 7.85;N, 0.12.

Step 4

4-[4-(2-Benzyl-4,5-dimethyl-furan-3-carbonyl)-2,6-diispropyl-phenoxysulfonyl]-2-hydroxy-benzoicAcid

The title compound was prepared according to the procedure in Example 4using(2-benzyl-4,5-dimethyl-furan-3-yl)-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone(0.300 g, 0.768 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.218g, 0.922 mmol) to give 0.04 g (9%) of the title compound as a tan solid,mp 142-143° C.; ¹H NMR (DMSO-d6) δ 1.04 (d, 12H), 1.81 (s, 3H), 2.19 (s,3H), 3.07 (septet, 2H), 3.81 (s, 2H), 6.95-6.97 (m, 2H), 7.14-7.20 (m,3H), 7.40-7.46 (m, 2H), 7.47 (s, 2H), 8.03 (d, 1H). IR (KBr) 3400, 2950,1675, 1375, 1180 cm⁻¹. mass spectrum (EI), m/z 590 (M+). Anal. Calcd.for C₃₃H₃₄O₈S.1.1H₂O: C, 64.92; H, 5.98; N, 0.00. Found: C, 64.92; H,5.76; N, −0.03.

EXAMPLE 6

4-[5′-(2-Ethyl-benzofuran-3-carbonyl)-[1,1′;3′,1″]terphenyl-2′-yloxysulfonyl]-2-hydroxy-benzoicAcid Sodium Salt

Step 1

3,5-Diiodo-4(2-methoxyethoxymethoxy)benzaldehyde

The title compound was prepared according to the procedure in Example 2,step 2 using 3,5-diiodo-4-hydroxybenzaldehyde (10.03 g, 26.83 mmol), 60%NaH/mineral oil (1.395 g, 34.87 mmol) and MEM chloride (4.902 mL, 42.92mmol) to give 12.81 g, of the title compound. ¹H NMR (DMSO-d6) δ 3.27(s, 3H), 3.54 (t, 2H), 4.02 (t, 2H), 5.24 (s, 2H), 8.34 (s, 2H), 9.84(s, 1H).

Step 2

2′-(2-Methoxyethoxymethoxy)-[1,1′;3′1″]terphenyl-5′-carbaldehyde

The title compound was prepared according to the procedure in Example 2,step 3 using 3,5-diiodo-4-(2-methoxyethoxymethoxy)benzaldehyde (4.029 g,8.721 mmol), phenylboronic acid (2.339 g, 19.19 mmol), palladium(II)acetate (39.16 mg, 0.174 mmol) in DME:H₂O. Purification on BiotageKP-Sil eluting with 15% EtOAc/pet. ether gave 1.803 g, (57%) of thetitle compound. ¹H NMR (DMSO-d6) δ 2.78-2.82 (m, 2H), 2.89-2.92 (m, 2H),3.01 (s, 3H), 4,42 (s, 2H), 7.40-7.54 (m, 6H), 7.62-7.65 (m, 4H), 7.91(s, 2H), 10.06 (s, 1H).

Step 3

2′-(2-Methoxyethoxymethoxy)-[1,1′;3′,1″]terphenyl-5′-carboxylic Acid

At ambient temperature, to a stirred mixture of silver (I) oxide (0.570g, 2.46 mmol) in H₂O (9.8 mL) was added NaOH (0.983 g, 24.6 mmol) andthe reaction was heated at 50° C. After 0.5 h, to the reaction was addeda solution of2′-(2-methoxyethoxymethoxy)-[1,1′;3′,1″]terphenyl-5′-carbaldehyde (1.78g, 4.92 mmol) in THF (9.8 mL) and the reaction was heated at 90° C. for1 h. To the reaction was added silver (I) oxide (0.570 g, 2.46 mmol),NaOH (0.983 g, 24.6 mmol) and H₂O (10.0 mL). The reaction was heated at90° C. for 16 h. The reaction was filtered through a celite pad, rinsingwith hot H₂O (3×). The filtrate was washed with ether (3×), acidifiedwith 2N HCl (pH 2) and extracted with EtOAc. The organic extracts weredried (MgSO₄) and concentrated to give 1.73 g (93%) of the titlecompound. ¹H NMR (DMSO-d6) δ 2.77-2.80 (m, 2H), 2.88-2.91 (m, 2H), 3.01(s, 3H), 4.39 (s, 2H), 7.39-7.52 (m, 6H), 7.59-7.62 (m, 4H), 7.89 (s,2H), 13.07 (s, 1H).

Step 4

2′-(2-Methoxyethoxymethoxy)-[1,1′;3′,1″]terphenyl-5′-carboxylic AcidMethyl Ester

At 0° C., to a stirred solution of2′-(2-methoxyethoxymethoxy)-[1,1′;3′,1″]terphenyl-5′-carboxylic acid(1.72 g, 4.55 mmol) in THF (4.55 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene. After 0.5 h, to the reaction wasadded iodomethane and the reaction was stirred for 16 h, eventuallywarming to ambient temperature. The reaction was filtered and thefiltrate concentrated. The crude product was dissolved in EtOAc, washedsequentially with sat. aq. NaHCO₃ (3×), with 1 N HCl (3×), brine (3×),dried (K₂CO₃) and concentrated. Purification on Biotage KP-Sil elutingwith 20% acetone/hexane gave 1.641 g (92%) of the title compound as ayellow oil. ¹H NMR (DMSO-d6) δ 2.77-2.80 (m, 2H), 2.88-2.91 (m, 2H),3.01 (s, 3H), 3.87 (s, 3H), 4.40 (s, 2H), 7.40-7.53 (m, 6H), 7.60-7.62(m, 4H), 7.90 (s, 2H).

Step 5

2′-Hydroxy-[1,1′;3′1″]terphenyl-5′-carboxylic Acid Methyl Ester

At ambient temperature, to a stirred solution of2′-(2-methoxyethoxymethoxy)-[1,1′;3′,1″]terphenyl-5′-carboxylic acidmethyl ester (1.608 g, 4.098 mmol) in CH₂Cl₂ (16.08 mL) was addedportionwise trifluoroacetic acid (16.08 mL). After 1 h, the reaction wasdiluted with ether (100 mL), washed sequentially with H₂O (3×), withsat. aq. NaHCO₃ (3×), with brine (3×), dried (MgSO₄) and concentrated togive 1.240 g (99%) of the title compound as a white solid. ¹H NMR(DMSO-d6) δ 3.83 (s, 3H), 7.39-7.50 (m, 6H), 7.55-7.57 (m, 4H), 7.78 (s,2H), 9.28 (s, 1H).

Step 6

2′-Methoxy-[1,1′;3′,1″]terphenyl-5′-carboxylic Acid Methyl Ester

At ambient temperature, to a stirred mixture containing2′-hydroxy-[1,1′;3′,1″]terphenyl-5′-carboxylic acid methyl ester (1.232g, 4.049 mmol) and K₂CO₃ (0.6155 g, 4.454 mmol) in N,N-DMF (10.1 mL) wasadded iodomethane (0.353 mL, 5.67 mmol). After 18 h, the reaction wasdiluted with H₂O (100 mL) and the reaction was stirred vigorously. Theresulting precipitate was collected, dissolved in CH₂Cl₂, dried (K₂CO₃)and concentrated to give 1.167 g, (99%) of the title compound. ¹H NMR(DMSO-d6) δ 3.16 (s, 3H), 3.87 (s, 3H), 7.41-7.53 (m, 6H), 7.58-7.60 (m,4H), 7.89 (s, 2H).

Step 7

2′-Methoxy-[1,1′;3′,1″]terphenyl-5′-carboxylic Acid

At ambient temperature, to a stirred solution of2′-methoxy-[1,1′;3′,1″]terphenyl-5′-carboxylic acid methyl ester (1.148g, 3.606 mmol) in THF (36.06 mL) was added 1N KOH (36.06 mL) and thereaction was stirred for 16 h. The reaction was heated at 100° C. for anadditional 24 h. The reaction was cooled to ambient temperature, dilutedwith ether (100 mL) and extracted with 0.1N NaOH. The aqueous extractswere washed with ether (3×), acidified with 6N HCl and extracted withEtOAc. The organic extracts were dried (MgSO₄) and concentrated to give1.043 g (95%) of the title compound. ¹H NMR (DMSO-d6) δ 3.15 (s, 3H),7.40-7.52 (m, 6H), 7.58-7.60 (m, 4H), 7.88 (s, 2H), 13.04 (s, 1H).

Step 8

(2-Ethyl-benzofuran-3-yl)-(2′-methoxy-[1,1′;3′,1″]terphenyl-5′-yl)-methanone

The title compound was prepared according to the procedure in Example 5,step 2 using 2′-methoxy-[1,1′;3′,1″]terphenyl-5′-carboxylic acid (1.031g, 3.388 mmol), oxalyl chloride (0.325 mL, 3.727 mmol), commercial2-ethylbenzofuran (0.4953 g, 3.388 mmol) and tin (IV) chloride (0.436mL, 3.727 mmol) in CH₂Cl₂. Purification on Biotage KP-Sil eluting with3% EtOAc/pet. ether gave 1.070 g, (73%) of the title compound. ¹H NMR(DMSO-d6) δ 1.24 (t, 3H), 2.90 (quartet, 2H), 3.21 (s, 3H), 7.30-7.67(m, 14H), 7.75 (s, 2H).

Step 9

(2-Ethyl-benzofuran-3-yl)-(2′-hydroxy-[1,1′;3′,1″]terphenyl-5′-yl)-methanone

At −78° C., to a stirred solution of(2-ethyl-benzofuran-3-yl)-(2′-methoxy-[1,1′;3′,1″]terphenyl-5′-yl)-methanone(1.07 g, 2.47 mmol) in CH₂Cl₂ (10.1 mL) was added dropwise 1M borontribromide/ CH₂Cl₂ (5.2 mL). After the addition was complete, the dryice/acetone bath was replaced with an ice water bath and the reactionwas stirred for 72 h, eventually warming to ambient temperature. Thereaction was carefully quenched with crushed ice, diluted with H₂O (16mL ) and extracted with ether. The ethereal extracts were dried (MgSO₄)and concentrated. Purification on Biotage KP-Sil eluting with 15%acetone/hexane gave 0.86 g, (83%) of the tide compound as a white solid,mp 142-143° C. ¹H NMR (DMSO-d6) δ 1.24 (t, 3H), 2.90 (quartet, 2H),7.28-7.66 (m, 16H), 9.37 (s, 1H). IR (KBr) 3200, 2950, 1625, 1560 and1175 cm⁻¹. mass spectrum (EI), m/z 418 (M+). Anal. Calcd. forC₂₉H₂₂O_(3.)0.35H₂O: C, 82.00; H, 5.39; N, 0.00. Found: C, 82.06; H,5.40; N, 0.07.

Step 10

4-[5′-(2-Ethyl-benzofuran-3-carbonyl)-[1,1′;3′,1″]terphenyl-2′-yloxysulfonyl]-2-hydroxy-benzoicAcid Sodium Salt

The free acid of the title compound was prepared according to theprocedure in Example 4 using(2-ethyl-benzofuran-3-yl)-(2′-hydroxy-[1,1′;3′,1″]terphenyl-5′-yl)-methanone(0.307 g, 0.734 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.208g, 0.880 mmol). Purification on Dynamax C18 (85% CH₃CN/H₂O) followed bycrystallization (EtOAc/hexane) gave 0.204 g, (45%) of the free acid as awhite solid.

At ambient temperature, to a stirred solution of the free acid (0.204 g,0.329 mmol) in MeOH (10 mL) was added 25% wt. sodium methoxide/methanol(71.1 mg, 0.329 mmol). After 0.5 h, the reaction was concentrated togive 0.210 g (100%) of the title compound as a yellow solid, mp 211-212°C. ¹H NMR (DMSO-d6) δ 1.25 (t, 3H), 2.45 (quartet, 2H), 6.24-6.26 (m,2H), 7.28-7.33 (m, 6H), 7.35-7.47 (m, 8H), 7.65-7.67 (m, 1H), 7.73 (s,2H). mass spectrum (−ESI), m/z 617 (M−H). Anal. Calcd. for C₃₆H₂O, SNa1.3H₂O: C, 65.11; H, 4.19; N, 0.00. Found: C, 64.96; H, 4.23; N, 0.10.

EXAMPLE 7

4-[5-(2-Benzyl-4,5-dimethyl-furan-3-carbonyl)-3-methyl-biphenyl-2-yloxysulfonyl-2-hydroxy-benzoicAcid Sodium Salt

Step 1

3-Iodo-4-hydroxy-5-methylbenzaldehyde

At 5° C., to a stirred solution containing commercial4-hydroxy-3-methylbenzaldehyde (4.65 g, 34.1 mmol) and sodium hydroxide(2.73 g, 68.25 mmol) in MeOH (171 mL) was added iodine (10.8 g, 42.7mmol). The reaction was stirred for 16 h, eventually warming to ambienttemperature. The reaction was quenched with 1N HCl (200 mL) andextracted with ether. The ethereal extracts were washed with 10% Na₂S₂O₃(3×), with brine (3×), dried (MgSO₄) and concentrated. Purification onBiotage KP-Sil eluting with 70% CH₂Cl₂/pet. ether to give 7.28 g (81%)of the title compound as a yellow solid. ¹H NMR (DMSO-d6) δ 2.30 (s,3H), 7.65 (d, J=1.02 Hz, 1H), 8.09 (d, J=1.91 Hz, 1H), 9.74 (s, 1H),10.25 (s, 1H).

Step 2

3-Iodo-4-methoxy-5-methylbenzaldehyde

At 5° C., to a stirred solution of 3-iodo-4-hydroxy-5-methylbenzaldehyde(3.53 g, 13.5 mmol) in THF (67.4 mL) was added 60% sodiumhydride/mineral oil (0.701 g, 17.5 mmol). After 0.5 h, to the reactionwas added dropwise iodomethane (1.34 mL, 21.6 mmol). After 2 h, thereaction was heated at 60° C. After 3 days, the reaction was cooled toambient temperature, quenched with H₂O (100 mL) and extracted withether. The ethereal extracts were washed with 1N NaOH (3×), with brine(3×), dried (ACO₃) and concentrated. Purification on Biotage KP-Sileluting with 15% acetone/hexane gave 2.24 g (60%) of the title compound.¹H NMR (DMSO-d6) δ 2.37 (s, 3H), 3.77 (s, 3H), 7.78 (s, 1H), 8.17 (s,1H), 9.86 (s, 1H).

Step 3

6-Methoxy-5-methyl-biphenyl-3-carbaldehyde

The title compound was prepared according to the procedure in Example 2,step 3 using 3-iodomethoxy-5-methylbenzaldehyde (2.24 g, 8.11 mmol),phenylboronic acid (1.09 g, 8.92 mmol), palladium(II) acetate (36.4 mg,0.162 mmol) and barium hydroxide octahydrate (3.83 g, 12.2 mmol) inDME:H₂O. Purification on Biotage KP-Sil eluting with 15% acetone/hexanegave 1.54 g (84%) of the title compound as a yellow oil. ¹H NMR(DMSO-d6) δ 2.37 (s, 3H), 3.39 (s, 3H), 7.42-7.59 (m, 5H), 7.74-7.79 (m,2H), 9.96 (s, 1H).

Step 4

6-Methoxy-5-methyl-biphenyl-3-carboxylic Acid

The title compound was prepared according to the procedure in Example 6,step 3 using 6-methoxy-5-methyl-biphenyl-3-carbaldehyde (1.53 g, 6.77mmol), silver (I) oxide (1.56 g, 6.77 mmol) and NaOH (2.71 g, 67.7 mmol)to give 1.46 g (89%) of the title compound as a white solid, mp 165-168°C. ¹H NMR (DMSO-d6) δ 2.34 (s, 3H), 3.36 (s, 3H), 7.38-7.55 (m, 5H),7.71 (d, 1H), 7.81 (dd, 1H). IR (KBr) 3400, 2950, 1700, 1600 and 1410cm⁻¹. mass spectrum (EI), m/z 242 (M+). Anal. Calcd. forC₁₅H₁₄O₃.0.2H₂O: C, 73.27; H, 5.91; N, 0.00. Found: C, 73.21; H, 5.93;N, 0.17.

Step 5

8(2-Benzyl-4,5-dimethyl-thiophen-3-yl)-(5-methyl-6-methoxy-biphen-3-yl)-methanone

The title compound was prepared according to the procedure in Example 5,step 2 using 6-methoxy-5-methyl-biphenyl-3-carboxylic acid (1.39 g, 5.74mmol), 2-benzyl-4,5-dimethylfuran (1.15 g, 5.74 mmol), oxalyl chloride(0.550 mL, 6.32 mmol), tin (IV) chloride (0.739 mL, 6.32 mmol) andN,N-DMF (2 drops) in CH₂Cl₂. Purification on Biotage KP-Sil eluting with5% EtOAc/pet. ether gave 1.69 g (71%) of the title compound as a brownoil. ¹H NMR (DMSO-d6) δ 1.84 (s, 3H), 2.18 (s, 3H), 2.29 (s, 3H), 3.38(s, 3H), 3.85 (s, 2H), 7.04-7.07 (m, 2H), 7.17-7.26 (m, 3H), 7.38-7.48(m, 6H), 7.58 (d, 1H).

Step 6

2-Benzyl-4.5-dimethyl-thiophen-3-yl)-(5-methyl-6-hydroxy-biphen-3-yl)-methanone

The title compound was prepared according to the procedure in Example 5,step 3 using(2-benzyl-4,5-dimethyl-thiophen-3-yl)-(5-methyl-6-methoxy-biphen-3-yl)-methanone(1.68 g, 4.09 mmol) and 1M boron tribromide/CH₂Cl₂ (8.58 mL).Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 1.29g (80%) of the title compound. ¹H NMR (DMSO-d6) δ 1.83 (s, 3H), 2.17 (s,3H), 2.25 (s, 3H), 3.85 (s, 2H), 7.07-7.10 (m, 2H), 7.14-7.26 (m, 3H),7.33-7.43 (m, 6H), 7.54 (d, 1H), 9.31 (s, 1H).

Step 7

4-[5-(2-Benzyl-4,5-dimethyl-furan-3-carbonyl)-3-methyl-biphenyl-2-yloxysulfonyl]-2-hydroxy-benzoicAcid Sodium Salt

The free acid of the title compound was prepared according to theprocedure in Example 4 using(2-benzyl-4,5-dimethyl-thiophen-3-yl)-(5-methyl-6-hydroxy-biphen-3-yl)-methanone(0.302 g, 0.762 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.216g, 0.991 mmol). Purification on Dynamax C18 (80% CH₃CN/H₂O) gave 0.15 gof the free acid.

The sodium salt was prepared according to the procedure in Example 6,step 10 using the free acid (0.15 g, 0.251 mmol) and 25% wt. sodiummethoxide (54 mg, 0.251 mmol) in MeOH (7.6 mL) to give the titlecompound as a yellow solid, mp 187-190° C. ¹H NMR (DMSO-d6) δ 1.84 (s,3H), 2.18 (s, 3H), 2.23 (s, 3H), 3.83 (s, 2H), 6.52 -6.56 (m, 2H),7.01-7.04 (m, 2H), 7.14-7.24 (m, 8H), 7.38 (d, 1H), 7.56-7.60 (m, 2H).IR (KBr) 3400, 2950, 1640, 1590 and 1430 cm⁻¹. mass spectrum (−ESI) m/z595 (M−H). Anal. Calcd. for C₃₄H₂₇O₈SNa 1.6 H₂O: C, 63.07; H, 4.70; N,0.00. Found: C, 63.06; H, 4.60; N, 0.04.

Example 8

4-[4-(4,5-Dimethyl-2-naphthalen-2-ylmethyl-furan-3-carbonyl)-2,6-diisopropyl-phenoxysulfonyl]-2-hydroxy-benzoicAcid

Step 1

2-Naphthalen-2-ylmethyl-4,5-dimethylfuran

The title compound was prepared according to the procedure in Example 5,step 1 using 2,3-dimethylfuran, 2-(bromomethyl)naphthalene and 1.6Mn-BuLi/hexanes in THF. ¹H NMR (DMSO-d6) δ 1.89 (s, 3H), 2.15 (s, 3H),4.08 (s, 2H), 5.95 (s, 1H), 7.40 (d, 1H), 7.45-7.57 (m, 2H), 7.77 (s,1H), 7.83-7.91 (m, 3H).

Step 2

(2-Naphthalen-2-ylmethyl-4,5-dimethyl-furan-3-yl)-(3,5-diisopropyl-4-methoxy-phenyl)-methanone

The title compound was prepared according to the procedure in Example 5,step 2 using 3,5-diisopropyl-p-anisic acid (0.93 g, 3.95 mmol, RN-117439-59-5), oxalyl chloride (0.377 mL, 4.33 mmol),N,N-dimethylformamide (2 drops), tin (IV) chloride (0.507 mL, 4.33 mmol)and 2-naphthalen-2-ylmethyl-4,5-dimethylfuran (0.93 g, 3.94 mmol) inCH₂Cl₂. Purification on Biotage KP-Sil eluting with a 2 & 4% EtOAc/pet.ether step gradient gave 0.357 g (20%) of the title compound. ¹H NMR(DMSO-d6) δ 1.14 (d, 12H), 1.82 (s, 3H), 2.20 (s, 3H), 3.27 (septet,2H), 3.74 (s, 3H), 4.02 (s, 2H), 7.19 (dd, 1H), 7.45-7.52 (m, 5H),7.76-7.79 (m, 3H).

Step 3

(2-Naphthalen-2-ylmethyl-4,5-dimethyl-furan-3-yl)-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone

The title compound was prepared according to the procedure in Example 5,step 3 using(2-naphthalen-2-ylmethyl-4,5-dimethyl-furan-3-yl)-(3,5-diisopropyl-4-methoxy-phenyl)-methanone(1.04 g, 2.29 mmol) and 1M boron tribromide/CH₂Cl₂ (4.81 mL) in CH₂Cl₂.Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave0.542 g (54%) of the title compound. ¹H NMR (DMSO-d6) δ 1.12 (d, 12H),1.82 (s, 3H), 2.18 (s, 3H), 3.31 (septet, 2H), 4.02 (s, 2H), 7.22 (dd,1H), 7.43-7.50 (m, 4H), 7.55 (s, 1H), 7.76-7.86 (m, 3H), 9.12 (s, 1H).

Step 4

4-[4-(4,5-Dimethyl-2-naphthalen-2-ylmethyl-furan-3-carbonyl)-2,6-diisopropyl-phenoxysulfonyl]-2-hydroxy-benzoicAcid

The title compound was prepared according to the procedure in Example 4using(2-naphthalen-2-ylmethyl-4,5-dimethyl-furan-3-yl)-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone(0.300 g, 0.681 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.209g, 0.885 mmol). Purification on Dynamax C18 (80% CH₃CN/H₂O) gave 0.240 g(55%) of the title compound as a yellow solid, mp 130-135° C. ¹H NMR(DMSO-d6) δ 1.03 (d, 12H), 1.83 (s, 3H), 2.20 (s, 3H), 3.09 (septet,2H), 4.01 (s, 2H), 7.18 (d, 1H), 7.43-7.48 (m, 5H), 7.51 (s, 2H),7.77-7.79 (m, 2H), 7.82-7.86 (m, 1H), 8.05 (d, 1H). IR (KBr) 3400, 2950,1700, 1375 and 1190 cm⁻¹. mass spectrum (−ESI) m/z 639 (M−H). Anal.Calcd. for C₃₇H₃₆O₈S: C, 69.36; H, 5.66; N, 0.00. Found: C, 69.04; H,5.77; N, 0.04.

EXAMPLE 9

4-{4-[2-(2-Bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2,6-diisopropyl-phenoxysulfonyl}-2-hydroxy-benzoicAcid

Step 1

2-(2-Bromo-benzyl)-4,5-dimethyl-furan

The title compound was prepared according to the procedure in Example 5,step 1 using commercial 2,3-dimethylfuran (1.00 g, 10.4 mmol),commercial 2-bromobenzylbromide (2.60 g, 10.4 mmol) and 1.6Mn-BuLi/hexanes (4.16 mL, 10.4 mmol) in THF. Purification on BiotageKP-Sil eluting with 100% pet. ether gave 1.14 g (41%) of the titlecompound as a clear oil. ¹H NMR (DMSO-d6) δ 1.84 (s, 3H), 2.11 (s, 3H),3.96 (s, 2H), 5.81 (s, 1H), 7.19 (dt, 1H), 7.26-7.37 (m, 2H), 7.60 (dd,1H).

Step 2

2-(2-Bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-methoxy-phenyl)-methanone

The title compound was prepared according to the procedure in Example 5,step 2 using 3,5-diisopropyl-p-anisic acid (0.983 g, 4.16 mmol,RN-117439- 59- 5), oxalyl chloride (0.398 mL, 4.56 mmol),N,N-dimethylformamide (2 drops), tin (IV) chloride (0.535 mL, 4.58 mmol)and 2-(2-bromo-benzyl)4,5-dimethyl-furan (1.10 g, 4.16 mmol) in CH₂Cl₂.Purification on Biotage KP-Sil eluting with 3% EtOAc/pet. ether gave0.990 g (49%) of the title compound as a clear oil. ¹H NMR (DMSO-d6) δ1.15 (d, 12H), 1.84 (s, 3H), 2.18 (s, 3H), 3.27 (septet, 2H), 3.73 (s,3H), 3.91 (s, 2H), 7.12-7.16 (m, 2H), 7.29 (t, 1H, 7.44 (s, 2H), 7.50(d, 1H).

Step 3

[2-(2-Bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone

The title compound was prepared according to the procedure in Example 5,step 3 using[2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-methoxy-phenyl)-methanone(0.973 g, 2.01 mmol) and 1M boron tribromide/CH₂Cl₂ (4.23 mL) in CH₂Cl₂.Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave0.679 g (72%) of the title compound. ¹H NMR (DMSO-d6) δ 1.13 (d, 12H),1.82 (s, 3H), 2.18 (s, 3H), 3.31 (septet, 2H), 3.94 (s, 2H), 7.12-7.17(m, 2H), 7.30 (dt, 1H), 7.42 (s, 2H), 7.52 (d, 1H), 9.10 (s, 1H).

Step 4

4-[4-[2-(2-Bromo-benzyl)4,5-dimethyl-furan-3-carbonyl]-2.6-diisopropyl-phenoxysulfonyl]-2-hydroxy-benzoicAcid

The title compound was prepared according to the procedure in Example 4using[2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone(0.300 g, 0.639 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.197g, 0.831 mmol). Purification on Dynamax C18 (90% CH₃CN/H₂O) gave 0.20 g(47%) of the title compound as a yellow solid, mp 90-95” C. ¹H NMR(DMSO-d6) δ 1.06 (d, 12H), 1.85 (s, 3H), 2.19 (s, 3H), 3.07 (septet,2H), 3.91 (s, 2H), 7.14-7.16 (m, 2H), 7.29 (dt, 1H), 7.44 (d, 1H),7.47-7.52 (m, 4H), 8.05 (d, 1H). IR (KBr) 3400, 2950, 1690, 1380 and1190 cm⁻¹. mass spectrum (−ESI) m/z 667/669 (M−H). Anal. Calcd. forC₃₃H₃₃BrO₈S: C, 59.19; H, 4.97; N, 0.00. Found: C, 58.82; H, 5.13; N,0.13.

EXAMPLE 10

4-{4-[2-(3-Bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2,6-diisopropyl-phenoxysulfonyl]-2-hydroxy-benzoicAcid

Step 1

2-(3-Bromo-benzyl)-4,5-dimethyl-furan

The title compound was prepared according to the procedure in Example 5,step 1 using commercial 2,3-dimethylfuran (5.00 g, 52.0 mmol),commercial 3-bromobenzylbromide (13.0 g, 52.0 mmol) and 2.5Mn-BuLi/hexanes (20.8 mL, 52.0 mmol) in THF. Purification on BiotageKP-Sil eluting with 1% EtOAc/pet. ether gave 12.63 g (85%) of the titlecompound. ¹H NMR (DMSO-d6) δ 1.85 (s, 3H), 2.10 (s, 3H), 3.86 (s, 2H),5.90 (s, 1H), 7.21-7.30 (m, 2H), 7.34-7.47 (m, 2H).

Step 2

[2-(3-Bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-methoxy-phenyl)-methanone

The title compound was prepared according to the procedure in Example 5,step 2 using 3,5-diisopropyl-p-anisic acid (1.02 g, 4.32 mmol,RN-117439-59-5), oxalyl chloride (0.415 mL, 4.75 mmol),N,N-dimethylformamide (2 drops), tin (IV) chloride (0.556 mL, 4.75 mmol)and 2-(3-bromo-benzyl)-4,5-dimethyl-furan (1.15 g, 4.32 mmol) in CH₂Cl₂.Purification on Biotage KP-Sil eluting with 3% EtOAc/pet. ether gave1.36 g (65%) of the title compound as a yellow clear oil. ¹H NMR(DMSO-d6) δ 1.17 (d, 12H), 1.80 (s, 3H), 2.20 (s, 3H), 3.28 (septet,2H), 3.74 (s, 3H), 3.87 (s, 2H), 7.06 (d, 1H), 7.19 (d, 1H), 7.24 (s,1H), 7.38 (dd, 1H), 7.46 (s, 2H).

Step 3

[2-(3-Bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3.5-diisopropyl-4-hydroxy-phenyl)-methanone

The title compound was prepared according to the procedure in Example 5,step 3 using[2-(3-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-methoxy-phenyl)-methanone(1.34 g, 2.78 mmol) and 1M boron tribromide/CH₂Cl₂ (5.84 mL) in CH₂Cl₂.Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave0.995 g (73%) of the title compound. ¹H NMR (DMSO-d6) δ 1.14 (d, 12H),1.80 (s, 3H), 2.19 (s, 3H), 3.32 (septet, 2H), 3.87 (s, 2H), 7.09 (d,1H), 7.22 (t, 1H), 7.26 (s, 1H), 7.39 (d, 1H), 7.43 (s, 2H), 9.13 (s,1H). IR (KBr) 3350, 2950, 1580, 1560 and 1325 cm⁻¹. mass spectrum (EI)m/z 468 (M+). Anal. Calcd. for C₂₆H₂₉BrO₃: C, 66.53; H, 6.23; N, 0.00.Found: C, 66.50; H, 6.22; N, 0.08.

Step 4

4{4-[2-(3-Bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2,6-diisopropyl-phenoxysulfonyl}-2-hydroxy-benzoicAcid

The title compound was prepared according to the procedure in Example 4using[2-(3-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone(0.300 g, 0.639 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.197g, 0.831 mmol). Purification on Dynamax C18 (95% CH₃CN₃H₂O) gave 0.23 g(54%) of the title compound as an off white solid, mp 148° C. ¹H NMR(DMSO-d6) δ 1.06 (d, 12H), 1.80 (s, 3H), 2.21 (s, 3H), 3.08 (septet,2H), 3.87 (s, 2H), 7.04 (d, 1H), 7.21 (t, 1H), 7.25 (s, 1H), 7.38 (d,1H), 7.44 (s, 1H), 7.48 (dd, 1H), 7.51 (s, 2H), 8.06 (d, 1H). IR (KBr)3400, 2950, 1680, 1650 and 1180 cm⁻¹. mass spectrum (−ESI) m/z 667(M−H). Anal. Calcd. for C₃₃H₃₃BrO₈S: C, 59.19; H, 4.97; N, 0.00. Found:C, 58.86; H, 4.93; N, 0.07.

EXAMPLE 11

4-{4-[2-(4-Bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2,6-diisopropyl-phenoxysulfon}-2-hydroxy-benzoicAcid

Step 1

2-(4-Bromo-benzyl)-4,5-dimethyl-furan

The title compound was prepared according to the procedure in Example 5,step 1 using commercial 2,3-dimethylfuran (5.00 g, 52.0 mmol),commercial 4-bromobenzylbromide (13.0 g, 52.0 mmol) and 2.5Mn-BuLi/hexanes (20.8 mL, 52.0 mmol) in THF. Purification on BiotageKP-Sil eluting with 1% EtOAc/pet. ether gave 5.72 g (41%) of the titlecompound. ¹H NMR (DMSO-d6) δ 1.84 (s, 3H), 2.09 (s, 3H), 3.83 (s, 2H),5.87 (s, 1H), 7.17 (d, 2H), 7.49 (d, 2H).

Step 2

[2-(4-Bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-methoxyphenyl)-methanone

The title compound was prepared according to the procedure in Example 5,step 2 using 3,5-diisopropyl-p-anisic acid (1.03 g, 4.35 mmol, RN-117439-59-5), oxalyl chloride (0.417 mL, 4.79 mmol),N,N-dimethylformamide (2 drops), tin (IV) chloride (0.560 mL, 4.79 mmol)and 2-(4-bromo-benzyl)-4,5-dimethyl-furan (1.15 g, 4.35 mmol) in CH₂Cl₂.Purification on Biotage KP-Sil eluting with 3% EtOAc/pet. ether gave1.63 g (77%) of the title compound as a yellow clear oil. ¹H NMR(DMSO-d6) δ 1.16 (d, 12H), 1.80 (s, 3H), 2.19 (s, 3H), 3.28 (septet,2H), 3.74 (s, 3H), 3.83 (s, 2H), 6.98 (d, 2H), 7.41 (dd, 2H), 7.44 (s,2H).

Step 3

[2-(4-Bromo-benzyl-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone

The title compound was prepared according to the procedure in Example 5,step 3 using[2-(4-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-methoxy-phenyl)-methanone(1.61 g, 3.32 mmol) and 1M boron tribromide/CH₂Cl₂ (6.97 mL) in CH₂Cl₂.Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 1.37g (88%) of the title compound. ¹H NMR (DMSO-d6) δ 1.12 (d, 12H), 1.78(s, 3H), 2.17 (s, 3H), 3.30 (septet, 2H), 3.81 (s, 2H), 7.01 (dd, 2H),7.40 (s, 2H), 7.42 (d, 2H), 9.10 (s, 1H). IR (KYBr) 3400, 2950, 1640,1580 and 1310 cm⁻¹mass spectrum (EI) m/z 468 (M+). Anal. Calcd. forC₂₆H₂₉BrO₃: C, 66.53; H, 6.23; N, 0.00. Found: C, 66.57; H, 6.39; N,0.05.

Step 4

4-{4-[2-(4-Bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2,6-diisopropyl-phenoxysulfonyl]-2-hydroxy-benzoicAcid

The title compound was prepared according to the procedure in Example 4using[2-(4-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone(1.30 g, 2.77 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (1.00 g,4.22 mmol). Purification on Dynamax C18 (90% CH₃CN/H₂O) gave 0.98 g(53%) of the title compound as an off white solid, mp 165-168° C. ¹H NMR(DMSO-d6) δ 1.05 (d, 12H), 1.80 (s, 3H), 2.19 (s, 3H), 3.06 (septet,2H), 3.81 (s, 2H), 6.92 (d, 2H), 7.39 (dd, 2H), 7.44 (s, 1H), 7.45 (s,2H), 7.48 (d, 1H), 8.05 (d, 1H). IR (KBr) 3400, 2950, 1680, 1375 and1190 cm⁻¹. mass spectrum (−ESI) m/z 667 (M−H). Anal. Calcd. forC₃₃H₃₃BrO₈S: C, 59.20; H, 4.97; N, 0.00. Found: C, 59.18; H, 5.21; N,0.08.

EXAMPLE 12

4-{4-[2-(2-Benzyl-benzo[b]thiophen-3-yl)-ethyl]-phenoxysulfonyl}-2-hydroxy-benzoicAcid

Step 1

2-Benzyl-benzo[b]thiophene-3-carboxaldehyde

Tin chloride (14.0 mL, 119.6 mmol) was added dropwise into a cold (−20°C.) solution of 2-benzyl-benzo[b]thiophene (13.4 g, 59.8 mmol) indichloromethane (150.0 mL). After 1 h, to the reaction was addeddropwise dichloromethyl methyl ether (119.6 mmol). The mixture wasallowed to gradually come to 0° C., and then stirred for 20 hours. Themixture was carefully poured into HCl (2 N) and ice, and extracted withethyl ether. The ethereal extracts were dried (MgSO₄) and concentratedto give 12.9 g (85%) of the title compound after crystallization fromethyl ether/hexanes, yellow solid mp 86-88° C.; mass spectrum m/z 252(M⁺). Anal. Calcd. for C₁₆H₁₂O₅: C 76.16; H, 4.79. Found: C, 75.77; H,4.85

Step 2

trans-2-Benzyl-3-[2-(4-methoxy-phenyl)-vinyl]-benzo[b]thiophene &cis-2-Benzyl-3-[2-(4-methoxy-phenyl)-vinyl]-benzo[b]thiophene

At −78° C., to a stirred suspension of(4-methoxybenzyl)triphenylphosphonium chloride (0.996 g, 2.38 mmol) inTHF was added dropwise 1.6M n-BuLi/hexanes (1.36 mL, 2.18 mmol). After 1h, to the reaction was added dropwise to a solution of2-benzyl-benzo[b]thiophene-3-carboxaldehyde (5.00 g, 26.8 mmol) in THFthat had been previously cooled to −78° C. The reaction was allowed towarm to ambient temperature and stirred for 2 h. The reaction wasquenched with H₂O (200 mL), extracted with CH₂Cl₂ and concentrated.Purification on Biotage KP-Sil eluting with a 1% EtOAc/pet. ether gavethe title compounds as white solids. Analytical data trans isomer; mp79-81° C. ¹H NMR (DMSO-d6) δ 3.66 (s, 3H), 4.01 (s, 2H), 6.55 (d, 1H),6.71 (d, 2H), 6.88 (d, 1H), 7.01 (d, 2H), 7.13-7.29 (m, 7H), 7.39-7.42(m, 1H), 7.83-7.85 (m, 1H). IR (KBr) 3100, 2950, 1600, 1510 and 1250cm⁻¹. mass spectrum (EI) m/z 356 (M+). Anal. Calcd. for C₂₄H₂₀OS 0.2H₂O:C, 80.05; H, 5.71; N, 0.00. Found: C, 80.22; H, 5.86; N, 0.04.Analytical data cis isomer; mp 95-98° C. ¹H NMR (DMSO-d6) δ 3.78 (s,3H), 4.41 (s, 2H), 6.95 (d, 2H), 7.07 (d, 1H), 7.21-7.24 (m, 1H),7.29-7.43 (m, 7H), 7.61 (d, 2H), 7.87 (dd, 1H), 8.06 (d, 1H). IR (KBr)3050, 2900, 1700, 1500 and 1250 cm⁻¹. mass spectrum (EI) m/z 356 (M+).Anal. Calcd. for C₂₄H₂₀OS.0.1H₂O: C, 80.46; H, 5.68; N, 0.00. Found: C,80.40; H, 5.95; N, 0.01.

Step 3

2-Benzyl-3-[2-(4-methoxy-phenyl)-ethyl]-benzo[b]thiophene

At ambient temperature, a mixture of cis andtrans-2-benzyl-3-[2-(4-methoxy-phenyl)-vinyl]-benzo[b]thiophene in EtOAcand 10% palladium on carbon was stirred under H₂ (atmosphericconditions). The reaction was filtered and the filtrate concentrated togive the title compound as a white solid, mp 68-70° C. ¹H NMR;consistent. mass spectrum (EI) m/z 358 (M+). Anal. Calcd. for C₂₄H₂₂OS:C, 80.41; H, 6.19; N, 0.00. Found: C, 80.20; H, 6.18; N, 0.03.

Step 4

4-[2-(2-Benzyl-benzo[b]thiophen-3-yl)-ethyl]-phenol

The title compound was prepared according to the procedure in Example 5,step 3 using 2-benzyl-3-[2-(4-methoxy-phenyl)-ethyl]-benzo[b]thiophene(5.50 g, 15.3 mmol) and 1M boron tribromide/CH₂Cl₂C (49.1 mL) in CH₂Cl₂.Purification on silica gel eluting with a 5 & 10% EtOAc/pet. ether stepgradient gave the tide compound as an oil. ¹H NMR; consistent. massspectrum (EI) m/z 344 (M+).

Step 5

4-{4-[2-(2-Benzyl-benzo[b]thiophen-3-yl)-ethyl]-phenoxysulfonyl}-2-hydroxy-benzoic Acid

The title compound was prepared according to the procedure in Example 4using 4-[2-(2-benzyl-benzo[b]thiophen-3-yl)-ethyl]-phenol (0.400 g, 1.16mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.550 g, 2.32 mmol).Purification on 2% H₃PO₄/MeOH treated silica gel, eluting with 20%EtOAc/hexane gave the title compound as an off white solid, mp 57-59° C.¹H NMR (DMSO-d6) δ 2.74 (t, 2H), 3.09 (t, 2H), 4.00 (s, 2H), 6.97 (d,2H), 7.19-7.23 (m, 5H), 7.27-7.38 (m, 6H), 7.76 (d, 1H), 7.83 (dd, 1H),7.98 (d, 1H). IR (KBr) 3400, 2950, 1675, 1390 and 1190 cm⁻¹. massspectrum (−ESI) m/z 543 (M−H).

EXAMPLE 13

4-{4-[2-(4-Bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-2-hydroxy-benzoicAcid

Step 1

[2-(4-Bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3-cyclopyl-4-methoxy-phenyl)-methanone

The title compound was prepared according to the procedure in Example 5,step 2 using 3-cyclopentyl-p-anisic acid (2.04 g, 9.24 mmol,RN-59216-82-9), oxalyl chloride (0.887 mL, 10.2 mmol),N,N-dimethylformamide (2 drops), tin (IV) chloride (1.19 mL, 10.2 mmol)and 2-(4-bromo-benzyl)-4,5-dimethyl-furan (2.45 g, 9.24 mmol) in CH₂Cl₂.Purification on Biotage KP-Sil eluting with 4% EtOAc/pet. ether gave3.39 g (78%) of the title compound. ¹H NMR (DMSO-d6) δ 1.38-1.47 (m,2H), 1.60-1.73 (m, 4H), 1.79 (s, 3H), 1.90-1.94 (m, 2H), 2.18 (s, 3H),3.21 (quintet, 1H), 3.82 (s, 2H), 3.88 (s, 3H), 7.02-7.08 (m, 3H), 7.44(d, 2H), 7.55-7.61 (m, 2H).

Step 2

[2-(4-Bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3-cyclopentyl-4-hydroxy-phenyl)-methanone

The title compound was prepared according to the procedure in Example 5,step 3 using[2-(4bromo-benzyl)4,5-dimethyl-furan-3-yl]-(3-cyclopentyl-4-methoxy-phenyl)-methanone(3.38 g, 7.23 mmol) and 1M boron tribromide/CH₂Cl (15.2 mL) in CH₂Cl₂.Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 1.66g (51%) of the title compound. ¹H NMR (DMSO-d6) δ 1.39-1.48 (m, 2H),1.59-1.65 (m, 2H), 1.68-1.76 (m, 2H), 1.79 (s, 3H), 1.88-1.95 (m, 2H),2.18 (s, 3H), 3.18 (quintet, 1H), 3.81 (s, 2H), 6.87 (d, 1H), 7.04 (d,2H), 7.43-7.47 (m, 3H), 7.53 (s, 1H), 10.35 (s, 1H). IR (KBr) 3300,2950, 1650, 1575 and 1280 cm⁻¹. mass spectrum (+ESI) m/z 453 (M+H).Anal. Calcd. for C₂₅H₂,BrO 3: C, 66.23; H, 5.56; N, 0.00. Found: C,66.12; H, 5.49; N, 0.03.

Step 3

4-{4-[2-(4-Bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-2-hydroxy-benzoicAcid

The title compound was prepared according to the procedure in Example 4using[2-(4-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3-cyclopentyl-4-hydroxy-phenyl)-methanone(0.203 g, 0.448 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.319g, 1.34 mmol). Purification on Dynamax C18 (85% CH₃CN/H₂O) gave 0.221 g(49%) of the title compound as a brown solid, mp 188-192° C. ¹H NMR(DMSO-d6) δ 1.26-1.32 (m, 2H), 1.49-1.57 (m, 2H), 1.64-1.74 (m, 4H),1.77 (s, 3H), 2.18 (s, 3H), 2.96 (quintet, 1H), 3,79 (s, 2H), 6.96 (d,2H), 7.23 (d, 1H), 7.36-7.43 (m, 4H), 7.53-7.56 (m, 2H), 8.00 (d, 1H).IR (KBr) 3400, 2950, 1690, 1390 and 1190 cm⁻¹. mass spectrum (−ESI) m/z651 (M−H). Anal. Calcd. for C₃₂H₂₉BrO₈ S: C, 58.81; H, 4.47; N, 0.00.Found: C, 58.45; H, 4.54; N, 0.07.

EXAMPLE 14

4-{4-[2-(2-Butyl-benzofuran-3-yl)-ethyl]-phenoxysulfonyl}-2-hydroxy-benzoicAcid

Step 1

2-n-Butylbenzofuran-3-carboxaldehyde

At ambient temperature, phosphorous oxychloride (180 mL, 1.94 mol) wascarefully added dropwise to N,N-DMF (200 mL). After the addition wascomplete the reaction was cooled to 10° C. To the reaction was addeddropwise commercial 2-butylbenzofuran (240 mL, 1.37 mol) and thereaction was heated to 85° C. for 70 h. The reaction was cooled toambient temperature and carefully quenched with H₂O (600 mL), adjustedto pH 5 with NaOAc and extracted with ether. The ethereal extracts werewashed with H₂O, dried (MgSO₄ ) and concentrated. The crude product waspurified on silica gel eluting with a 0% & 20% CH₂Cl₂hexane stepgradient to give 186 g (84%) of the title compound as a yellow oil. ¹HNMR consistent.

Step 2

cis-2-Butyl-3-[2-(4-methoxy-phenyl)-vinyl]-benzofuran &trans-2-Butyl-3-[2-(4-methoxy-phenyl)-vinyl]-benzofuran

The title compound was prepared according to the procedure in Example12, step 2 using (4-methoxybenzyl) triphenylphosphonium chloride (13.5g, 32.2 mmol), 1.6M n-BuLi/hexanes (18.5 mL, 29.5 mmol) and2-n-butylbenzofuran-3-carboxaldehyde (5.00 g, 26.8 mmol). Purificationon Biotage KP-Sil eluting with a 10 & 20% toluene/pet. ether stepgradient gave the title compounds as oils. Analytical data cis isomer:¹H NMR consistent. IR (KBr) 2950, 1600, 1560, 1450 and 1250 cm¹. massspectrum (EI) m/z 306 (M+). Analytical data trans isomer: ¹ H NMRconsistent. mass spectrum (EI) m/z 306 (M+).

Step 3

2-Butyl-3-[2-(4-methoxy-phenyl)-ethyl]-benzofuran

At ambient temperature, a solution containingcis-2-butyl-3-[2-(4-methoxy-phenyl)-vinyl]-benzofuran (0.400 g, 1.31mmol) in EtOAc (5 mL) and 10% palladium on carbon (200 mg) was stirredunder H₂ (atmospheric conditions). The reaction was filtered and thefiltrate concentrated to the title compound as a clear oil. ¹H NMR(DMSO-d6) δ 0.83 (t, 3H), 1.20 (sextet, 2H), 1.37 (quintet, 2H),2.49-2.52 (m, 2H, with DMSO), 2.78-2.85 (m, 4H), 3.68 (s, 3H), 6.78 (d,2H), 7.03 (d, 2H), 7.17-7.21 (m, 2H), 7.41-7.43 (m, 1H), 7.54-7.56 (m,1H). IR (KBr) 2950, 1610, 1510, 1450 and 1250 cm⁻¹. mass spectrum (EI)m/z 308 (M+). Anal. Calcd. for C₂₁H₂₄O₂: C, 81.78; H, 7.84; N, 0.00.Found: C, 81.55; H, 7.57; N, 0.10.

Step 4

4-[2-(2-Butyl-benzofuran-3-yl)-ethyl]-phenol

The title compound was prepared according to the procedure in Example 5,step 3 using 2-butyl-3-[2-(4-methoxy-phenyl)-ethyl]-benzofuran (0.300 g,0.973 mmol) and 1M boron tribromide/CH₂Cl₂ (3.1 1 mL) in CH₂Cl₂.Purification on silica gel eluting with 50% EtOAc/pet. ether gave thetitle compound as a dark oil. ¹H NMR (DMSO-d6) δ 0.84 (t, 3H), 1.22(sextet, 2H), 1.41 (quintet, 2H), 2.52 (t, 2H), 2.74 (t, 2H), 2.81 (t,2H), 6.61 (d, 2H), 6.91 (d, 2H), 7.15-7.21 (m, 2H), 7.40-7.43 (m, 1H),7.52-7.54 (m, 1H), 9.10 (s, 1H). IR (KBr) 3400, 2950, 1610, 1510 and1450 cm⁻¹. mass spectrum (FAB) m/z 295 (M+H).

Step 5

4-{4-[2-(2-Butyl-benzofuran-3-yl)-ethyl]-phenoxysulfonyl}-2-hydroxy-benzoicAcid

The title compound was prepared according to the procedure in Example 4using 4-[2-(2-butyl-benzofuran-3-yl)-ethyl]-phenol (0.410 g, 1.36 mmol)and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.644 g, 2.72 mmol).Purification on 2% H₃PO₄/MeOH treated silica gel, eluting withEtOAc/hexane gave 0.571 g (85%) of the title compound as a light brownsolid, mp 93-95° C. ¹H NMR consistent. mass spectrum (−ESI) m/z 493(M−H).

EXAMPLE 15

4-{4-[(2-Butyl-benzofuran-3-ylmethyl)-amino]-phenoxysulfonyl}-2-hydroxy-benzoicAcid

Step 1

4-[(2-Butyl-benzofuran-3-ylmethyl]-amino]-phenol

At ambient temperature, to a stirred solution containing2-n-butylbenzofuran-3-carboxaldehyde (0.888 g, 4.77 mmol) and4-aminophenol hydrochloride in MeOH (7 mL) was added sodiumcyanoborohydride (0.330 g, 5.25 mmol). After 24 h, the reaction wascarefully quenched with 3N HCl, diluted with H₂O and extracted withCH₂Cl₂. The organic extracts were washed with sat. aq. NaHCO₃, dried andconcentrated. Purification on silica gel eluting with a 20 & 40%EtOAc/pet. ether step gradient gave the title compound as a pale yellowsolid. ¹H NMR (CDCl₃) δ 0.93 (t, 3H), 1.38 (sextet, 2H), 1.70 (quintet,2H), 2.79 (t, 2H), 4.27 (s, 1H), 4.35 (br. s, 1H), 6.62 (d, 2H), 6.75(d, 2H), 7.18-7.26 (m, 3H), 7.41 (d, 1H), 7.54 (d, 1H).

Step 2

4-{4-[(2-Butyl-benzofuran-3-ylmethyl)-amino]-phenoxysulfonyl}-2-hydroxy-benzoicAcid

The title compound was prepared according to the procedure in Example 4using 4-[(2-butyl-benzofuran-3-ylmethyl)-amino]-phenol (0.500 g, 1.69mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.401 g, 1.69 mmol).Purification on 2% H₃PO₄/MeOH treated silica gel, eluting with 25%EtOAc/hexane gave 0.571 g (85%) of the title compound as a dark yellowsolid, mp 75-77° C. ¹H NMR (DMSO-d6) δ 0.86 (t, 3H), 1.31 (sextet, 2H),1.60 (quintet, 2H), 2.80 (t, 2H), 4.23 (s, 2H), 6.54 (d, 2H), 6.72 (d,2H), 7.14-7.22 (m, 2H), 7.26-7.30 (m, 2H), 7.45 (dd, 1H), 7.58 (dd, 1H),7.95 (d, 1H). IR (KBr) 3400, 2950, 1600, 1510 and 1380 cm⁻¹. massspectrum (−ESI) m/z 494 (M−H).

EXAMPLE 16

4-[4-(2-Butyl-benzofuran-3-carbonyl)-phenoxysulfonyl]-2-hydroxy-benzoicAcid

The title compound was prepared according to the procedure in Example 4using commercial 2-n-butyl-3-(4-hydroxybenzoyl)benzofuran (1.00 g, 3.40mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (1.61 g, 6.79 mmol).Purification on .2% H₃PO₄/MeOH treated silica gel, eluting withEtOAc/hexane gave 0.185 g (11%) of the title compound as an off whitesolid, mp 143-145° C. ¹H NMR (DMSO-d6) δ 0.76 (t, 3 H), 1.12-1.22 (m,2H), 1.60 (quintet, 2H), 2.69 (t, 2H), 7.21-7.38 (m, 7H), 7.61 (d, 1H),7.76 (d, 2H), 7.98 (d, 1H). IR (KBr) 2950, 1690, 1600, 1380 and 1150cm⁻¹. mass spectrum (+ESI) m/z 495 (M+H). Anal. Calcd. forC₂₆H₂₂O₈S.0.2H₂O: C, 62.24; H, 4.58; N, 0.00. Found: C, 62.38; H, 4.59;N, 0.13.

EXAMPLE 17

4-[4-(2-Benzyl-4,5-dimethyl-furan-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl]-2-hydroxy-benzoicAcid

Step 1

(2-Benzyl-4,5-dimethyl-furan-3-yl)-(3-cyclopentyl-4-methoxy-phenyl)-methanone

The title compound was prepared according to the procedure in Example 5,step 2 using 3-cyclopentyl-p-anisic acid (10.0 g, 45.5 mmol,RN-59216-82-9), oxalyl chloride (4.4 mL, 50.6 mmol),N,N-dimethylformamide (2 drops), tin (IV) chloride (15.8 mL, 49.6 mmol)and 2-benzyl-4,5-dimethyl-furan (10.1 g, 54.3 mmol) in CH₂Cl₂ to give18.8 g (crude) of the title compound. ¹H NMR (DMSO-d6) consistent.

Step 2

(2-Benzyl-4,5-dimethyl-furan-3-yl)-(3-cyclopentyl-4-hydroxy-phenyl)-methanone

The tide compound was prepared according to the procedure in Example 5,step 3 using(2-benzyl-4,5-dimethyl-furan-3-yl)-(3-cyclopentyl-4-methoxy-phenyl)-methanone(17.7 g, 45.5 mmol) and 1M boron tribromide/CH₂Cl₂ (34.8 mL) in CH₂Cl₂.Purification on Biotage KP-Sil eluting with a 2, 5 & 10% EtOAc/pet.ether step gradient gave 6.15 g (36%) of the title compound. ¹H NMR(DMSO-d6) δ 1.40-1.46 (m, 2H), 1.59-1.72 (m, 4H), 1.78 (s, 3H),1.90-1.94 (m, 2H), 2.16 (s, 3H), 3.18 (quintet, 1H), 3.81 (s, 2H), 6.87(d, 1H), 7.06 (d, 2H), 7.16-7.25 (m, 3H), 7.46 (dd, 1H), 7.55 (s, 1H),10.33 (s, 1H).

Step 3

4-[4-(2-Benzyl-4,5-dimethyl-furan-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl]-2-hydroxy-benzoicAcid

The title compound was prepared according to the procedure in Example 4using(2-benzyl-4,5-dimethyl-furan-3-yl)-(3-cyclopentyl-4-hydroxy-phenyl)-methanone(0.509 g, 1.36 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.645g, 2.72 mmol). Purification on 2% H₃PO₄/MeOH treated silica gel, elutingwith 20% EtOAc/hexane gave 0.430 g (55%) of the title compound a paleyellow solid, mp 80-85° C. ¹H NMR (DMSO-d6) δ 1.23-1.34 (m, 2H),1.45-1.59 (m, 2H), 1.61-1.74 (m, 4H), 1.76 (s, 3H), 2.16 (s, 3H), 2.95(quintet, 1H), 3.78 (s, 2H), 6.98 (d, 2H), 7.13-7.25 (m, 4H), 7.36-7.38(m, 2H), 7.44-7.57 (m, 2H), 7.97 (d, 1H). IR (KBr) 3400, 2950, 1690,1580, 1480 and 1190 cm⁻¹. mass spectrum (−ESI) m/z 573 (M−H). Anal.Calcd. for C₃₂H₃₀O₈S.0.2H₂O: C, 66.88; H, 5.26; N, 0.00. Found: C.,66.53; H, 5.40; N, 0.07.

EXAMPLE 18

4-[4-(2-Benzyl-4,5-dimethyl-thiophene-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl]-2-hydroxy-benzoicAcid

Step 1

2,3-Dimethylthiophene

A stirred mixture of commercial 3-methylthiophenecarboxaldehyde (20 g,0.159 mol), hydrazine hydrate (31 mL) and diethylene glycol (72 mL) wasrefluxed for 20 min. After cooling below 100° C., potassium hydroxide(22.9 g, 0.408 mol) was slowly added and the reaction mixture was heatedat 125-130° C. for 1.5 h. The reaction mixture was cooled to ambienttemperature, quenched with H₂O and extracted with ether. The combinedethereal extracts were washed with 5% aqueous HCl, brine, dried (MgSO₄)and concentrated. Purification on silica gel eluting with pentaneprovided the title compound as an oil (15.81 g, 89%): ¹H NMR (CDCl3) δ6.97 (d, 1H, J=8 Hz), 6.77 (d, 1H, J=8 Hz), 2.35 (s, 3H), 2.14 (s, 3H).

Step 2

2-Benzyl-4,5-dimethylthiophene

The title compound was prepared according to the procedure in Example 5,step 1 using 2,3-dimethylthiophene (5.00 g, 44.6 mmol), 2.5MBuLi/hexanes (17.9 mL, 44.6 mmol) and benzyl bromide (5.30 mL, 44.6mmol) in THF (44.6 mL). Purification on Biotage KP-Sil eluting with 1%EtOAc/pet ether gave 6.96 g (77%) of the title compound as an oil. ¹HNMR (DMSO-d6) δ 2.01 (s, 3H), 2.21 (s, 3H), 3.98 (s, 2H), 6.58 (s, 1H),7.18-7.37 (m, 5H).

Step 3

(2-Benzyl-4,5-dimethyl-thiophen-3-yl)-(3-cyclopentyl-4-methoxy-phenyl)-methanone

The title compound was prepared according to the procedure in Example 5,step 2 using 3-cyclopentyl-p-anisic acid (5.0 g, 22.7 mmol,RN-59216-82-9), oxalyl chloride (2.4 mL, 27.2 mmol),N,N-dimethylformamide (2 drops) tin(IV) chloride (2.9 mL, 25.0 mmol) and2-benzyl-2,3-dimethylthiophene (5.1 g, 25.0 mmol). Purification onsilica gel eluting 5% EtOAc/pet. ether gave 4.8 g (52%) of the titlecompound as an amber oil. (DMSO-d6) δ 7.61-7.54 (m, 2H), 7.24-7.14 (m,3H), 7.08-7.02 (m, 3H), 3.87 (s, 3H), 3.84 (s, 2H), 3.42-3.30 (m, 1H),2.26 (s, 3H), 2.00-1.85 (m, 2H), 1.81 (s, 3H), 1.74-1.58 (m, 4H),1.48-1.36 (m, 2H). mass spectrum (EI) m/z 404 (M+). Anal. Calc. forC₂₆H₂₈O₂S: C, 77.19, H, 6.98, N, 0.00. Found: C, 76.26, H, 7.24, N,0.04.

Step 4

(2-Benzyl-4,5-dimethyl-thiophen-3-yl)-(3-cyclopentyl-4-hydroxy-phenyl)-methanone

The title compound was prepared according to the procedure in Example 5,step 3 using(2-benzyl-4,5-dimethyl-thiophen-3-yl)-(3-cyclopentyl-4-methoxy-phenyl)-methanone(3.32 g, 8.20 mmol) and 1M boron tribromide/CH₂Cl₂ (1.6 mL) in CH₂Cl₂.Purification on Biotage KP-Sil eluting with a 2, 5 & 10% EtOAc/hexanestep gradient gave 0.63 g (18%) of the title compound. ¹H NMR (DMSO-d6)δ consistent.

Step 5

4-[4-(2-Benzyl-4,5-dimethyl-thiophene-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl]-2-hydroxy-benzoicAcid

The title compound was prepared according to the procedure in Example 4using(2-benzyl-4,5-dimethyl-thiophen-3-yl)-(3-cyclopentyl-4-hydroxy-phenyl)-methanone(0.505 g, 1.29 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.612g, 2.58 mmol). Purification on 2% H₃PO₄/MeOH treated silica gel, elutingwith 15% EtOAc/hexane gave 0.432 g (57%) of the title compound a paleyellow solid, mp 70-77° C. ¹H NMR (DMSO-d6) δ 1.29-1.34 (m, 2H),1.51-1.57 (m, 2H), 1.62-1.77 (m,4H), 1.79 (s, 3H), 2.25 (s, 3H), 2.99(quintet, 1H), 3.84 (s, 2H), 6.98 (d, 2H), 7.12-7.25 (m, 4H), 7.39 (d,2H), 7.52 (dd, 1H), 7.57 (d, 1H), 7.99 (d, 1H). IR (KBr) 3400, 2950,1690, 1390 and 1190 cm⁻¹. mass spectrum (+ESI) m/z 591 (M+H). Anal.Calcd. for C₃₂H₃₀O₇S₂.0.5H₂O: C, 64.09; H, 5.21; N, 0.00. Found: C,63.96; H, 5.30; N, 0.04.

EXAMPLE 19

4-[4-(2-Benzyl-4,5-dimethyl-furan-3-carbonyl)-2.6-diethyl-phenoxysulfonyl]-2-hydroxy-benzoicAcid

Step 1

4-Bromo-2,6-diethylbenzenediazonium Tetrafluoroborate

At 0° C., to a stirred solution of commercial 4-bromo-2,6-diethylaniline(10.0 g, 43.9 mmol) in absolute ethanol (219 mL) was added 48% aq.tetrafluoroboric acid (17.2 mL), followed by tert-butyl nitrite (5.7 mL,48.0 mmol). After 0.5 h, the reaction was poured into ice cold ether(877 mL). The resulting precipitate was washed with cold ether and driedto give 9.39 g (66%) of the title compound. ¹HNR: consistent.

Step 2

4-Bromo-2,6-diethylanisole

A stirred solution containing 4-bromo-2,6-diethylbenzenediazoniumtetrafluoroborate (17.25 g, 52.77 mmol) and freshly ground anhydrouszinc chloride (7.2 g, 52.9 mmol) in methanol (1.06 L) was refluxed for 6h. The reaction was cooled to ambient temperature, quenched with H₂O(1.2 L), saturated with solid sodium chloride and extracted with hexane.The combined organic extracts were sequentially washed with sat. aq.NaHCO₃ (1×100 mL), with H₂O (1×100 mL), with brine (1×100 mL), dried(Na₂SO₄) and concentrated to give 12.0 g (94%) of title compound. ¹HNMR: consistent. mass spectrum (EI), m/z 242 (M+).

Step 3

3,5-Diethyl-4-methoxybenzoic Acid

At −78° C., to a stirred solution of 4-bromo-2,6-diethylanisole (12.0 g,49.4 mmol) in THF (329 mL) was added dropwise n-butyllithium (27.2 mL,43.5 mmol). After 3h, the reaction was poured into crushed dry ice andallowed to warm to ambient temperature. The reaction mixture was dilutedwith EtOAc, concentrated, suspended in H₂O, acidified (pH 1), filteredand the collected solids washed with H₂O. The crude product was slurriedin hexane (15 mL), collected by filtration and dried to give 6.76 g(66%) of the title compound. ¹H NMR: consistent. IR (KBr) consistent.mass spectrum (EI), m/z 208 (M+). Anal. Calcd. for C₁₂H₁₆O₃: C, 69.21;H, 7.74; N, 0.00. Found: C, 69.28; H, 7.49; N, 0.07.

Step 4

(2-Benzyl-4.5-dimethyl-furan-3-yl)-(3.5-diethylmethoxy-phenyl)-methanone

The title compound was prepared according to the procedure in Example 5,step 2, using 3,5-diethyl-4-methoxybenzoic acid (10.66 g, 51.3 mmol),oxalyl chloride (4.90 mL, 56.3 mmol), N,N-DMF (2 drops), tin IV chloride(6.60 mL, 56.3 mmol) and 2-benzyl-4,5-dimethylfuran (11.4 g, 61.3 mmol)to give 22.0 g, of the title compound. ¹H NMR δ 1.13 (t, 6H), 1.83 (s,3H), 2.19 (s, 3H), 2.61 (q, 4H), 3.74 (s, 3H), 3.82 (s, 2H), 7.05 (d,2H), 7.23-7.27 (m, 3H), 7.42 (s, 2H). mass spectrum (EI), m/z 376 (M+).

Step 5

(2-Benzyl-4,5-dimethyl-furan-3-yl)-(3.5-diethyl-4-hydroxy-phenyl)-methanone

The title compound was prepared according to the procedure in Example 5,step 3 using(2-benzyl-4,5-dimethyl-furan-3-yl)-(3,5-diethyl-4-methoxy-phenyl)-methanone(19.3 g, 51.2 mmol) and 1M boron tribromide/CH₂Cl₂ (36.8 mL) in CH₂Cl₂.Purification on Biotage KP-Sil eluting with a 2 & 5% EtOAc/hexane stepgradient gave 7.07 g (37%) of the title compound. ¹H NMR (DMSO-d6) δ1.08 (t, 6H), 1.79 (s, 3H), 2.17 (s, 3H), 2.57 (q, 4H), 3.81 (s, 2H),7.06 (dd, 2H), 7.16-7.18 (m, 1H), 7.22-7.26 (m, 2H), 7.37 (s, 2H), 9.10(s, 1H). mass spectrum (EI), m/z 362 (M+).

Step 6

4-[4-(2-Benzyl-4,5-dimethyl-furan-3-carbonyl)-2,6-diethyl-phenoxysulfonyl]-2-hydroxy-benzoicAcid

The title compound was prepared according to the procedure in Example 4using(²-benzyl-4,5-dimethyl-furan-3-yl)-(3,5-diethyl-4-hydroxy-phenyl)-methanone(0.5 g, 1.38 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.65 g,2.74 mmol). Purification on 2% H₃PO₄/MeOH treated silica gel, elutingwith 10% EtOAc/hexane gave 0.251 g (32%) of the title compound as an offwhite solid, mp 143-147° C. ¹H NMR (DMSO-d6) δ 1.01 (t, 6H), 1.84 (s,3H), 2.20 (s, 3H), 2.51 (q, 4H, with DMSO peak), 3.81 (s, 2H), 7.01 (d,2H), 7.16-7.20 (m, 1H), 7.23-7.27 (m, 2H), 7.45 (s, 2H), 7.49-7.53 (m,2H), 8.06 (d, 1H). mass spectrum (−ESI), m/z 561 (M−H). Anal. Calcd. forC₃₁H₃₀O₈S: C, 66.18; H, 5.37; N, 0.00. Found: C, 65.80; H, 5.50; N,0.22.

EXAMPLE 20

4-{4-[2-(4-Bromo-benzyl)-4,5-dimethyl-thiophene-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-2-hydroxy-benzoicAcid

Step 1

2-(4-Bromobenzyl)-4,5-dimethylthiophene

The title compound was prepared according to the procedure in Example 5,step 1 using 2,3-dimethylthiophene (5.10 g, 45.5 mmol), 2.5MBuLi/hexanes (18.2 mL, 45.5 mmol) and 4-bromobenzyl bromide (11.4 g,45.5 mmol) in THF. Purification on Biotage KP-Sil eluting with 100% petether gave 7.74 g (60%) of the title compound. ¹H NMR: consistent.

Step 2

[2-(4-Bromobenzyl)-4,5-dimethyl-thiophen-3-yl]-(3-cyclopentyl-4-methoxy-phenyl)-methanone

The title compound was prepared according to the procedure in Example 5,step 2 using 3-cyclopentyl-p-anisic acid (3.50 g, 15.9 mmol,RN-59216-82-9), oxalyl chloride (1.52 mL, 17.5 mmol),N,N-dimethylformamide (2 drops) tin(IV) chloride (2.04 mL, 17.5 mmol)and 2-(4-bromobenzyl)4,5-dimethylthiophene (4.46 g, 15.9 mmol).Purification on silica gel eluting 5% EtOAc/pet. ether gave 4.05 g (53%)of the title compound as yellow oil. (DMSO-d6) δ 1.43-1.47 (m, 2H),1.61-1.75 (m, 4H), 1.81 (s, 3H), 1.91-1.99 (m, 2H), 2.28 (s, 3H), 3.24(quintet, 1H), 3.84 (s, 2H), 3.88 (s, 3H), 7.02 (d, 2H), 7.06 (d, 1H),7.40 (d, 2H), 7.52 (dd, 1H), 7.57 (d, 1H).

Step 3

[2-(4-Bromobenzyl)-4,5-dimethyl-thiophen-3-yl]-(3-cyclopentyl-4-hydroxy-phenyl)-methanone

The title compound was prepared according to the procedure in Example 5,step 3 using[2-(4-bromobenzyl)4,5-dimethyl-thiophen-3-yl]-(3-cyclopentyl-4-methoxy-phenyl)-methanone(4.05 g, 8.39 mmol) and 1M boron tribromide/CH₂Cl₂ (26.0 mL) in CH₂Cl₂.Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 2.90g (74%) of the title compound. (DMSO-d6) δ 1.41-1.48 (m, 2H), 1.59-1.74(m, 4H), 1.82 (s, 3H), 1.89-1.96 (m, 2H), 2.27 (s, 3H), 3.20 (quintet,1H), 3.84 (s, 2H), 6.88 (d, 1H), 7.03 (d, 2H), 7.39-7.43 (m, 3H), 7.54(d, 1H), 10.47 (s, 1H).

Step 4

4-{4-[2-(4-Bromo-benzyl)-4,5-dimethyl-thiophene-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-2-hydroxy-benzoicAcid

The title compound was prepared according to the procedure in Example 4using[2-(4-bromobenzyl)-4,5-dimethyl-thiophen-3-yl]-(3-cyclopentyl-4-hydroxy-phenyl)-methanone(1.01 g, 2.14 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (1.01 g,4.29 mmol). Purification on 2% H₃PO₄/MeOH treated silica gel, elutingwith a 15 & 25% EtOAc/hexane step gradient followed by crystallizationfrom ether/pet ether gave 0.549 g (38%) of the title compound as a tansolid, mp 165-170° C. ¹H NMR (DMSO-d6) δ 1.22-1.32 (m, 2H), 1.46-1.58(m, 2H), 1.61-1.76 (m, 4H), 1.78 (s, 3H), 2.26 (s, 3H), 2.97 (quintet,1H), 3.84 (s, 2H), 6.94 (d, 2H), 7.23 (d, 1H), 7.34-7.40 (m, 4H), 7.50(dd, 1H), 7.53 (d, 1H), 8.00 (d, 1H). IR (KBr) 3400, 2950, 1680, 1480,1390 and 1190 cm⁻¹. mass spectrum (−ESI) m/z 667 (M−H). Anal. Calcd. forC₃₂H₂₉BrO₇S₂: C, 57.40; H, 4.37; N, 0.00. Found: C, 57.47; H, 4.24; N,0.08.

EXAMPLE 21

4-{4-[2-(2-Bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-2-hydroxy-benzoicAcid

Step 1

2-(2-Bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3-cyclopentyl-4-methoxy-phenyl)-methanone

The title compound was prepared according to the procedure in Example 5,step 2 using 3-cyclopentyl-p-anisic acid (2.00 g, 9.08 mmol,RN-59216-82-9), oxalyl chloride (0.871 mL, 9.99 mmol),N,N-dimethylformamide (2 drops), tin (IV) chloride (1.17 mL, 4.58 mmol)and 2-(2-bromo-benzyl)-4,5-dimethyl-furan (2.41 g, 9.08 mmol) in CH₂Cl₂.Purification on Biotage KP-Sil eluting with 4% EtOAc/pet. ether gave2.82 g (66%) of the title compound as a clear oil. ¹H NMR (DMSO-d6) δ1.40-1.44 (m, 2H), 1.57-1.73 (m, 4H), 1.79 (s, 3H), 1.87-1.93 (m, 2H),2.16 (s, 3H), 3.21 (quintet, 1H), 3.86 (s, 3H), 3.93 (s, 2H), 7.04 (d,1H), 7.11-7.18 (m, 2H), 7.29 (t, 1H), 7.51 (dd, 1H), 7.54-7.60 (m, 2H).

Step 2

[2-(2-Bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3-cyclopentyl-4-hydroxy-phenyl)-methanone

The title compound was prepared according to the procedure in Example 5,step 3 using[2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3-cyclopentyl-4-methoxy-phenyl)-methanone(2.82 g, 6.03 mmol) and 1M boron tribromide/CH₂Cl₂ (18.7 mL) in CH₂Cl₂.Purification on Biotage KP-Sil eluting with a 2, 5 & 10% EtOAc/pet.ether step gradient gave 1.36 g (50%) of the title compound. (DMSO-d6) δ1.42-1.44 (m, 2H), 1.58-1.72 (m, 4H), 1.79 (s, 3H), 1.87-1.92 (m, 2H),2.16 (s, 3H), 3.17 (quintet, 1H), 3.92 (s, 2H), 6.85 (d, 1H), 7.12-7.17(m, 2H), 7.29 (t, 1H), 7.45 (dd, 1H), 7.50-7.52 (m, 2H), 10.31 (s, 1H).

Step 3

4-{4-[2-(2-Bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-2-hydroxy-benzoicAcid

The title compound was prepared according to the procedure in Example 4using[2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3-cyclopentyl-4-hydroxy-phenyl)-methanone(0.516 g, 1.14 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.540g, 2.28 mmol). Purification on 2% H₃PO₄/MeOH treated silica gel, elutingwith a 15 & 25% EtOAc/hexane step gradient gave 0.509 g (68%) of thetide compound as a brown solid, mp 72-82° C. ¹H NMR (DMSO-d6) δ1.25-1.34 (m, 2H), 1.50-1.55 (m, 2H), 1.62-1.74 (m, 4H), 1.77 (s, 3H),2.15 (s, 3H), 2.95 (quintet, 1H), 3.88 (s, 2H), 7.10-7.15 (m, 2H), 7.20(d, 1H), 7.27 (t, 1H), 7.35-7.37 (m, 2H), 7.48-7.58 (m, 3H), 7.96 (dd,1H). IR (KBr) 3400, 2950, 1690, 1390 and 1190 cm⁻¹. mass spectrum (−ESI)m/z 651 (M−H). Anal. Calcd. for C₃₂H₂₉BrO₈S.0.4H₂O: C, 58.17; H, 4.55;N, 0.00. Found: C, 58.20; H, 4.55; N, 0.03.

EXAMPLE 22

2-Acetoxy-4-[4-(2-benzyl-4,5-dimethyl-furan-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl]-benzoicAcid

A stirred solution containing4-[4-(2-benzyl-4,5-dimethyl-furan-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl]-2-hydroxy-benzoicacid (0.235 g, 0.409 mmol), acetic anhydride (3.3 mL) and magnesiumiodide (0.113 g, 0.409 mmol) in ether (8 mL) was refluxed for 0.5 h. Thereaction was allowed to cool to ambient temperature, quenched with H₂O(100 mL), extracted with ether and concentrated. The mixedanhydride/product was dissolved in THF (6 mL), treated with H₂O (6 mL)and refluxed for 0.5h. The reaction was allowed to cool to ambienttemperature, quenched with H₂O (100 mL), extracted with ether andconcentrated. Purification on 2% H₃PO₄/MeOH treated silica gel, elutingwith a 18 & 25% EtOAc/pet ether step gradient followed bycrystallization from acetone/hexane gave 0.201 g (80%) of the titlecompound as an off white solid, mp 55-90° C. ¹H NMR (DMSO-d6) δ1.23-1.32 (m, 2H), 1.50-1.53 (m, 2H), 1.64-1.72 (m, 4H), 1.76 (s, 3H),2.17 (s, 3H), 2.23 (s, 3H), 2.92 (quintet, 1H), 3.79 (s, 2H), 6.98-7.00(m, 2H), 7.15-7.23 (m, 4H), 7.53 (dd, 1H), 7.58 (d, 1H), 7.84 (d, 1H),7.88 (dd, 1 H), 8.12 (d, 1H) 13.7 (br s, 1H). mass spectrum (−ESI) m/z615 (M−H). Anal. Calcd. for C₃₄H₃₂O₉S.0.5H₂O: C, 65.27; H, 5.32; N,0.00. Found: C, 65.33; H, 5.30; N, 0.03.

EXAMPLE 23

2-Acetoxy-4-[4-(2-benzyl-4,5-dimethyl-thiophene-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl]-benzoicAcid

The title compound was prepared according to the procedure in Example 22using4-[4-(2-benzyl-4,5-dimethyl-thiophene-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl]-2-hydroxy-benzoicacid (0.233 g, 0.394 mmol), magnesium iodide (0.110 g, 0.394 mmol) andacetic anhydride (3.3 mL) in ether. Purification on 2% H₃PO₄/MeOHtreated silica gel, eluting with 18% EtOAc/pet ether followed by asecond chromatography on 2% H₃PO₄/MeOH treated silica gel, eluting with5% CH₃CN/CH₂Cl₂ gave 0.128 g (51%) of the title compound as a whitesolid, mp 94-96° C. ¹H NMR (DMSO-d6) δ 1.24-1.33 (m, 2H), 1.52-1.57 (m,2H), 1.61-1.76 (m, 4H), 1.79 (s, 3H), 2.23 (s, 3H), 2.26 (s, 3H), 2.94(quintet, 1H), 3.85 (s, 2H), 6.99-7.01 (m, 2H), 7.13 (m, 4H), 7.52 (dd,1H), 7.59 (d, 1H), 7.84 (d, 1H), 7.90 (dd, 1H), 8.14 (d, 1H), 13.8 (brs, 1H). mass spectrum (−ESI) m/z 631 (M−H). Anal. Calcd. forC₃₄H₃₂O₈S₂0.2H₂O: C, 64.17; H, 5.13; N, 0.00. Found: C, 64.06; H, 4.98;N, 0.04.

EXAMPLE 24

2-Acetoxy-4-{4-[2-(4-Bromo-benzyl)-4,5-dimethyl-thiophene-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-benzoicAcid

The title compound was prepared according to the procedure in Example 22using4-{4-[2-(4-bromo-benzyl)-4,5-dimethyl-thiophene-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-2-hydroxy-benzoicacid (0.211 g, 0.315=mol), magnesium iodide (0.0876 g, 0.315 mmol) andacetic anhydride (2.5 mL) in ether. Purification on 2% H₃PO₄/MeOHtreated silica gel, eluting with a 10 & 20% EtOAc/pet ether stepgradient followed by crystallization from acetone/hexane gave 0.185 g(57%) of the title compound as a white solid, mp 113-114° C. ¹H NMR(DMSO-d6) δ 1.27-1.34 (m, 2H), 1.51-1.58 (m, 2H), 1.63-1.78 (m, 4H),1.80 (s, 3H), 2.25 (s, 3H), 2.28 (s, 3H), 2.95 (quintet, 1H), 3.86 (s,2H), 6.97 (d, 2H), 7.24 (d, 1H), 7.38 (d, 2H), 7.52 (dd, 1H), 7.57 (d,1H), 7.86 (d, 1H), 7.92 (dd, 1H), 8.16 (d, 1H) 13.8 (br s, 1H). massspectrum (−ESI) m/z 709 (M−H). Anal. Calcd. for C₃₄H₃₁BrO₈S₂: C, 57.38;H, 4.39; N, 0.00. Found: C, 56.99; H, 4.38; N, 0.02.

EXAMPLE 25

2-Acetoxy-4-{4-[2-(2-Bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-benzoicAcid

The title compound was prepared according to the procedure in Example 22using4-{4-[2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-2-hydroxy-benzoicacid (0.318 g, 0.487 mmol), magnesium iodide (0.132 g, 0.475 mmol) andacetic anhydride (3.8 mL) in ether. Purification on 2% H₃PO₄/MeOHtreated silica gel, eluting with a 30% EtOAc/pet ether gave 0.083 g(25%) of the title compound as a solid, mp 79° C. ¹H NMR (DMSO-d6) δ1.27-1.33 (m, 2H), 1.51-1.54 (m, 2H), 1.63-1.73 (m, 4H), 1.79 (s, 3H),2.17 (s, 3H), 2.24 (s, 3H), 2.93 (quintet, 1H), 3.91 (s, 2H), 7.13-7.17(m, 2H), 7.21 (d, 1H), 7.30 (dt, 1H), 7.51 (dd, 1H), 7.55 (dd, 1H), 7.60(d, 1H), 7.85 (d, 1H), 7.90 (dd, 1H), 8.14 (d, 1H)13.8 (br s, 1H). massspectrum (−ESI) m/z 693/695 (M−H). Anal. Calcd. for C₃₄H₃₁BrO₉S: C,58.71; H, 4.49; N, 0.00. Found: C, 58.04; H, 4.52; N, 0.04.

EXAMPLE 26

2-Acetoxy-4{4-[2-(2-butyl-benzofuran-3-yl)-ethyl]-phenoxysulfonyl}-benzoic Acid

At ambient temperature, to a stirred solution containing4-{4-[2-(2-butyl-benzofuran-3-yl)-ethyl]-phenoxysulfonyl}-2-hydroxy-benzoicacid (0.298 g, 0.602 mmol) and acetic anhydride (1 mL) In EtOAc (2 mL)was added 4-(dimethylamino)pyridine (3.7 mg, 0.0301mmol). The reactionwas refluxed for 72 h. The reaction was cooled to ambient temperature,hydrolyzed with H₂O (5 mL) and stirred for 24 h. The reaction wasdiluted with EtOAc and the organic phase washed sequentially with H₂O(2×), brine (2×), dried (MgSO₄) and concentrated. Purification on 2%H₃PO₄/MeOH treated silica gel, eluting with a 10 & 20% EtOAc/pet etherstep gradient gave 0.122 g (76%) of the title compound as a yellowsolid, mp 54-57° C. ¹H NMR consistent. IR (KBr) 3400, 2900, 1700, 1380and 1190 cm¹. mass spectrum (−ESI) m/z 535 (M−H).

EXAMPLE 27

1-Methyl-1H-pyrazole-4-sulfonic acid4-[2-(4-bromo-benzyl)-4,5-dimethyl-thiophene-3-carbonyl]-2-cyclopentyl-phenylEster

Step 1

1-Methyl-1H-pyrazole-4-sulfonyl Chloride

At 5° C., to stirred chlorosulfonic acid (81.0 mL, 1.22 mol) wascautiously added N-methylpyrazole (25.0 g, 0.304 mol) over a 1 h period.After the addition was complete the reaction was stirred at ambienttemperature for 0.5 h, then heated at 110° C. for 16 h. At 5° C., to thereaction was added dropwise thionyl chloride (55.0 mL, 0.754 mol). Afterthe addition was complete the reaction was stirred at ambienttemperature for 1 h, then heated to reflux for 2 h. The reaction wascooled to 15° C. and carefully quenched (dropwise) into crushed ice. Thetitle compound was collected by filtration and dried in vacuo to give37.2 g (68%) of a white solid, mp 51° C. ¹H NMR (CDCl₃) δ 4.00 (s, 3H),7.95 (s, 1H), 8.03 (s, 3H). IR (KBr) 3125, 1700, 1520, 1400 and 1370cm⁻¹. mass spectrum (EI) m/z 180 (M+). Anal. Calcd. for C₄H₅ClN₂O₂S: C,26.60; H, 2.79; N, 15.51. Found: C, 26.25; H, 2.45; N, 15.16.

Step 2

1-Methyl-1H-pyrazole-4-sulfonic acid4-[2-(4-bromo-benzyl)-4,5-dimethyl-thiophene-3-carbonyl]-2-cyclopentyl-phenylEster

At ambient temperature, to a stirred solution of[2-(4-bromobenzyl)-4,5-dimethyl-thiophen-3-yl]-(3-cyclopentyl-4-hydroxy-phenyl)-methanone(0.283 g, 0.603 mmol) in N,N-DMF (3.0 mL) was added 60% sodiumhydride/mineral oil (24.1 mg, 0.603 mmol). After 0.5 h, to the reactionwas added a solution of 1-methyl-1H-pyrazole-4-sulfonyl chloride (0.120g, 0.664 mmol) in N,N-DMF (1.3 mL). After 3 h, the reaction was quenchedwith 1N NaOH (40 mL), extracted with CH₂Cl₂, dried (Na₂SO₄) andconcentrated. Purification on Biotage KP-Sil eluting with 20%acetone/hexane gave 0.202 g (55%) of the title compound as a yellowsolid, mp 55-60 C. (DMSO-d6) δ 1.29-1.34 (m, 2H), 1.59-1.79 (m, 6H),1.81 (s, 3H), 2.28 (s, 3H), 3.08 (quintet, 1H), 3.87 (s, 2H), 3.89 (s,3H), 6.98 (d, 2H), 7.32 (d, 1H), 7.39 (d, 2H), 7.53-7.57 (m, 2H), 7.97(s, 1H), 8.62 (s, 1H). IR (KBr) 3450, 2950, 1650, 1490, 1400, 1370 and1170 cm⁻¹. mass spectrum (+ESI) m/z 613/615 (M +H).

EXAMPLE 28

4-[4-(2-Butyl-benzofuran-3-ylmethyl)-phenoxysulfonyl]-2-hydroxy-benzoicAcid

Step 1

4-[(2-Butyl-benzofuran-3-yl)-hydroxy-methyl]-phenol

A solution containing commercial2-n-butyl-3-(4-hydroxybenzoyl)benzofuran (0.500 g, 17.0 mmol) andlithium aluminum hydride (34.0 mmol) in THF (84 mL) was refluxed for 3h. The reaction was cooled to −10° C., and carefully quenched with 0.1NNaOH and H₂O. The aqueous solution was extracted with ether andconcentrated. Purification on silica gel gave the title compound as awhite solid, mp 94-96° C. (DMSO-d6) δ 0.90 (t, 3H), 1.35 (sextet, 2H),1.64 (quintet, 2H), 2.84 (t, 2H), 5.67 (d, 1H), 5.87 (d, 1H), 6.69 (d,2H), 7.07 (t, 1H), 7.15 (dt, 1H), 7.22 (d, 2H), 7.40-7.43 (m, 2H), 9.24(s, 1H). IR (KBr) 3350, 2950, 1610, 1510 and 1450 cm⁻¹. mass spectrum(EI) m/z 296 (M+). Anal. Calcd. for C₁₉H₂₀O₃: C, 77.00; H, 6.80; N,0.00. Found: C, 75.63; H, 6.86; N, 0.04.

Step 2

4-(2-Butyl-benzofuran-3-ylmethyl)-phenol

At −10° C., to a stirred solution of4-[(2-butyl-benzofuran-3-yl)-hydroxy-methyl]-phenol (2.78 g, 9.39 mmol)in CH₃CN was added portionwise triethylsilane (two×1.50 mL, 18.78 mmoltotal, @ 0.5 h interval). To the reaction was added BF₃.Et₂O (1.19 mL,9.39 mmol) and the reaction was stirred for 10 min. The reaction wasquenched with sat. aq. K₂CO₃ and extracted with CH₂Cl₂. The organicextracts were washed with brine (3×), dried (MgSO₄) and concentrated.Purification on silica gel gave 2.35 g (89%) the title compound as awhite solid, mp 67-70° C. (DMSO-d6) δ 0.87 (t, 3H), 1.31 (sextet, 2H),1.62 (quintet, 2H), 2.78 (t, 2H), 3.84 (s, 2H), 6.64 (d, 2H), 7.02 (d,2H), 7.09 (dt, 1H), 7.16 (dt, 1H), 7.31 (d, 1H), 7.42 (d, 1H), 9.16 (s,1H). IR (KBr) 3300, 2950, 1610, 1510 and 1450 cm⁻¹. mass spectrum (EI)m/z 280 (M+

Step 3

4-[4-(2-Butyl-benzofuran-3-ylmethyl)-phenoxysulfonyl]-2-hydroxy-benzoicAcid

The title compound was prepared according to the procedure in Example 4using 4-(2-butyl-benzofuran-3-ylmethyl)-phenol (0.500 g, 1.78 mmol) and4-chlorosulphonyl-2-hydroxyobenzoic acid (0.844 g, 3.56 mmol).Purification on 2% H₃PO₄/MeOH treated silica gel, eluting withEtOAc/hexane gave 0.728 g (86%) of the title compound as an orangesolid, mp 135-138° C. ¹H NMR (DMSO-d6) δ 0.84 (t, 3H), 1.27 (sextet,2H), 1.58 (quintet, 2H), 2.76 (t, 2H), 3.97 (s, 2H), 6.96 (d, 2H), 7.10(dt, 1H), 7.17 (dt, 1H), 7.22-7.31 (m, 5H), 7.43 (d, 1H), 7.95 (d, 1H).IR (KBr) 3300, 2950, 1675, 1390 and 1175 cm⁻¹. mass spectrum (−ESI) m/z479 (M−H). Anal. Calcd. for C₂₆H₂₄O₇S.0.2H₂O: C, 64.50; H, 5.08; N,0.00. Found: C, 64.50; H, 5.07; N, 0.06.

What is claimed is:
 1. A compound of formula I having the structurewherein R¹ and R² are each, independently, hydrogen, alkyl of 1-6 carbonatoms, halogen, perfluoroalkyl of 1-6 carbon atoms, cycloalkyl of 3-8carbon atoms, phenyl or phenyl substituted with trifluoromethyl, chloro,methoxy, or trifluoromethoxy; R³ and R⁴ are each, independently,hydrogen, carboxyl, hydroxyl, hydoxyalkyl of 1-6 carbon atoms, alkoxy of1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, alkanoyloxy of2-7 carbon atoms, perfluoroalkanoyloxy of 2-7 carbon atoms, arylalkoxyof 7-15 carbon atoms, aryloxy of 6-12 carbon atoms, aroyloxy of 6-12carbon atoms, aryloxycarbonyl of 7-13 carbon atoms, alkoxycarbonyl of2-7 carbon atoms, perfluoroalkoxycarbonyl of 2-7 carbon atoms, alkyl of1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkylamino of 1-6carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group,mercapto, nitrile, nitro, amino, —NHSO₂CF₃, carbamoyl, carboxyaldehyde,halogen, acylamino, 3-hydroxy-cyclobut-3-ene-4-yl-1,2-dione; R⁵ ishydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms,naphthalenylmethyl, benzyl or benzyl substituted with halogen, R⁶ and R⁷are each, independently, hydrogen, alkyl of 1-6 carbon atoms, orperfluoroalkyl of 1-6 carbon atoms, or R⁶ and R⁷ may be taken togetheras a diene unit having the structure —CH═CH—CH═CH—; W is S or O, X is—NR⁸CH₂—, —NR⁸—, or O; R⁸ is hydrogen or alkyl; Y is carbonyl,methylene, ethyl, or —NHCH₂—; Z is pyridyl, thienyl, furyl, pyrrolyl; ora pharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1, wherein R¹ and R² are each, independently, hydrogen, alkyl of1-6 carbon atoms, halogen, perfluoroalkyl of 1-6 carbon atoms,cycloalkyl of 3-8 carbon atoms, phenyl or phenyl substituted withtrifluoromethyl, chloro, methoxy, or trifluoromethoxy; R³ and R⁴ areeach, independently, hydrogen, carboxyl, hydroxyl, alkoxy of 1-6 carbonatoms, perfluoroalkoxy of 1-6 carbon atoms, alkanoyloxy of 2-7 carbonatoms, perfluoroalkanoyloxy of 2-7 carbon atoms, aroyloxy of 6-12 carbonatoms, alkoxycarbonyl of 2-7 carbon atoms, aryloxycarbonyl of 7-13carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbonatoms, mercapto, nitrile, amino, —NHSO₂CF₃, carbamoyl, carboxyaldehyde,or acylamino of 2-7 carbon atoms; R⁵ is hydrogen, alkyl of 1-6 carbonatoms, naphthalenylmethyl, benzyl or benzyl substituted with halogen; R⁶and R⁷ are each, independently hydrogen or alkyl of 1-6 carbon atoms orR⁶ and R⁷ may be taken together as a diene unit having the structure—CH═CH—CH═CH—; X is —NHCH₂—, or O; or a pharmaceutically acceptable saltthereof.
 3. The compound according to claim 1, wherein R¹ and R² areeach, independently, hydrogen, iodo, phenyl, alkyl of 1-6 carbon atoms,bromo, or cycloalkyl of 3-8 carbon atoms; R³ and R⁴ are each,independently, hydrogen, carboxyl, hydroxyl, methyl, or acetoxy; R⁵ ishydrogen, alkyl of 1-6 carbon atoms, naphthalenylmethyl, benzyl orbenzyl substituted with bromo; R⁶ and R⁷ are each, independently,hydrogen or methyl, or R⁶ and R⁷ may be taken together as a diene unithaving the structure —CH═CH—CH═CH—; X is —NHCH₂—, or O; Y is carbonyl,methylene, —CH₂CH₂—, —NHCH₂—; Z is pyridyl; or a pharmaceuticallyacceptable salt thereof.
 4. A method of treating metabolic disordersmediated by insulin resistance or hyperglycemia in a mammal in needthereof which comprises administering to said mammal, a compound offormula I having the structure

wherein R¹ and R² are each, independently, hydrogen, alkyl of 1-6 carbonatoms, halogen, perfluoroalkyl of 1-6 carbon atoms, cycloalkyl of 3-8carbon atoms, phenyl or phenyl substituted with trifluoromethyl, chloro,methoxy, or trifluoromethoxy; R³ and R⁴ are each, independently,hydrogen, carboxyl, hydroxyl, hydoxyalkyl of 1-6 carbon atoms, alkoxy of1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, alkanoyloxy of2-7 carbon atoms, perfluoroalkanoyloxy of 2-7 carbon atoms, arylalkoxyof 7-15 carbon atoms, aryloxy of 6-12 carbon atoms, aroyloxy of 6-12carbon atoms, aryloxycarbonyl of 7-13 carbon atoms, alkoxycarbonyl of2-7 carbon atoms, perfluoroalkoxycarbonyl of 2-7 carbon atoms, alkyl of1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkylamino of 1-6carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group,mercapto, nitrile, nitro, amino, —NHSO₂CF₃, carbamoyl, carboxyaldehyde,halogen, acylamino, or 3-hydroxy-cyclobut-3-ene-4-yl-1,2-dione; R⁵ ishydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms,naphthalenylmethyl, benzyl or benzyl substituted with halogen, R⁶ and R⁷are each, independently, hydrogen, alkyl of 1-6 carbon atoms, orperfluoroalkyl of 1-6 carbon atoms, or R⁶ and R⁷ may be taken togetheras a diene unit having the structure —CH═CH—CH═CH—; W is S or O, X is—NR⁸CH₂—, —NR⁸—, or O; R⁸ is hydrogen or alkyl; Y is carbonyl,methylene, ethyl, or —NHCH₂—; Z is pyridyl, thienyl, furyl, pyrrolyl; ora pharmaceutically acceptable salt thereof.
 5. A method of treating orinhibiting type II diabetes in a mammal in need thereof which comprisesadministering to said mammal, a compound of formula I having thestructure

wherein R¹ and R² are each, independently, hydrogen, alkyl of 1-6 carbonatoms, halogen, perfluoroalkyl of 1-6 carbon atoms, cycloalkyl of 3-8carbon atoms, phenyl or phenyl substituted with trifluoromethyl, chloro,methoxy, or trifluoromethoxy; R³ and R⁴ are each, independently,hydrogen, carboxyl, hydroxyl, hydoxyalkyl of 1-6 carbon atoms, alkoxy of1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, alkanoyloxy of2-7 carbon atoms, perfluoroalkanoyloxy of 2-7 carbon atoms, arylalkoxyof 7-15 carbon atoms, aryloxy of 6-12 carbon atoms, aroyloxy of 6-12carbon atoms, aryloxycarbonyl of 7-13 carbon atoms, alkoxycarbonyl of2-7 carbon atoms, perfluoroalkoxycarbonyl of 2-7 carbon atoms, alkyl of1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkylamino of 1-6carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group,mercapto, nitrile, nitro, amino, —NHSO₂CF₃, carbamoyl, carboxyaldehyde,halogen, acylamino, or 3-hydroxy-cyclobut-3-ene-4yl-1,2-dione; R⁵ ishydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms,naphthalenylmethyl, benzyl or benzyl substituted with halogen, R⁶ and R⁷are each, independently, hydrogen, alkyl of 1-6 carbon atoms, orperfluoroalkyl of 1-6 carbon atoms, or R⁶ and R⁷ may be taken togetheras a diene unit having the structure —CH═CH—CH═CH—; W is S or O, X is—NR⁸CH₂—, —NR⁸—, or O; R⁸ is hydrogen or alkyl; Y is carbonyl,methylene, ethyl, or —NHCH₂—; Z is pyridyl, thienyl, furyl, or pyrrolyl;or a pharmaceutically acceptable salt thereof.
 6. A method of modulatingglucose levels in a mammal in need thereof which comprises administeringto said mammal, a compound of formula I having the structure

wherein R¹ and R² are each, independently, hydrogen, alkyl of 1-6 carbonatoms, halogen, perfluoroalkyl of 1-6 carbon atoms, cycloalkyl of 3-8carbon atoms, phenyl or phenyl substituted with trifluoromethyl, chloro,methoxy, or trifluoromethoxy; R³ and R⁴ are each, independently,hydrogen, carboxyl, hydroxyl, hydoxyalkyl of 1-6 carbon atoms, alkoxy of1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, alkanoyloxy of2-7 carbon atoms, perfluoroalkanoyloxy of 2-7 carbon atoms, arylalkoxyof 7-15 carbon atoms, aryloxy of 6-12 carbon atoms, aroyloxy of 6-12carbon atoms, aryloxycarbonyl of 7-13 carbon atoms, alkoxycarbonyl of2-7 carbon atoms, perfluoroalkoxycarbonyl of 2-7 carbon atoms, alkyl of1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkylamino of 1-6carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group,mercapto, nitrile, nitro, amino, —NHSO₂CF₃, carbamoyl, carboxyaldehyde,halogen, acylamino, 3-hydroxy-cyclobut-3-ene-4-yl-1,2-dione; R⁵ ishydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms,naphthalenylmethyl, benzyl or benzyl substituted with halogen, R⁶ and R⁷are each, independently, hydrogen, alkyl of 1-6 carbon atoms, orperfluoroalkyl of 1-6 carbon atoms, or R⁶ and R⁷ may be taken togetheras a diene unit having the structure —CH═CH—CH═CH—; W is S or O, X is—NR⁸CH₂—, —NR⁸—, or O; R⁸ is hydrogen or alkyl; Y is carbonyl,methylene, ethyl, or —NHCH₂—; Z is pyridyl, thienyl, furyl, pyrrolyl; ora pharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition which comprises a compound of formula I having the structure

wherein R¹ and R² are each, independently, hydrogen, alkyl of 1-6 carbonatoms, halogen, perfluoroalkyl of 1-6 carbon atoms, cycloalkyl of 3-8carbon atoms, phenyl or phenyl substituted with trifluoromethyl, chloro,methoxy, or trifluoromethoxy; R³ and R⁴ are each, independently,hydrogen, carboxyl, hydroxyl, hydoxyalkyl of 1-6 carbon atoms, alkoxy of1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, alkanoyloxy of2-7 carbon atoms, perfluoroalkanoyloxy of 2-7 carbon atoms, arylalkoxyof 7-15 carbon atoms, aryloxy of 6-12 carbon atoms, aroyloxy of 6-12carbon atoms, aryloxycarbonyl of 7-13 carbon atoms, alkoxycarbonyl of2-7 carbon atoms, perfluoroalkoxycarbonyl of 2-7 carbon atoms, alkyl of1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkylamino of 1-6carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group,mercapto, nitrile, nitro, amino, —NHSO₂CF₃, carbamoyl, carboxyaldehyde,halogen, acylamino, 3-hydroxy-cyclobut-3-ene-4-yl-1,2-dione; R⁵ ishydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms,naphthalenylmethyl, benzyl or benzyl substituted with halogen, R⁶ and R⁷are each, independently, hydrogen, alkyl of 1-6 carbon atoms, orperfluoroalkyl of 1-6 carbon atoms, or R⁶ and R⁷ may be taken togetheras a diene unit having the structure —CH═CH—CH═CH—; W is S or O, X is—NR⁸CH₂—, —NR⁸—, or O; R⁸ is hydrogen or alkyl; Y is carbonyl,methylene, ethyl, or —NHCH₂—; Z is pyridyl, thienyl, furyl, pyrrolyl; ora pharmaceutically acceptable salt thereof.